3-((Hetero-)Aryl)-Alkyl-8-Amino-2-Oxo-1,3-Diaza-Spiro-[4.5]-Decane Derivatives

ABSTRACT

The invention relates to 3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decane derivatives, their preparation and their use in medicine, particularly in the treatment of pain.

The invention relates to3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decanederivatives, their preparation and use in medicine, particularly invarious neurological disorders, including but not limited to pain,neurodegenerative disorders, neuroinflammatory disorders,neuropsychiatric disorders, substance abuse/dependence.

Opioid receptors are a group of Gi/o protein-coupled receptors which arewidely distributed in the human body. The opioid receptors are currentlysubdivided into four major classes, i.e. the three classical opioidreceptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, anddelta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1)receptor, which was more recently discovered based on its high homologywith said classical opioid receptors. After identification of theendogenous ligand of the ORL-1 receptor, known as nociceptin/orphaninFQ, a highly basic 17 amino acid peptide isolated from tissue extractsin 1995, the ORL-1 receptor was renamed “nociceptin opioid peptidereceptor” and abbreviated as “NOP-receptor”.

The classical opioid receptors (MOP, KOP and DOP) as well as the NOPreceptor are widely distributed/expressed in the human body, includingin the brain, the spinal cord, on peripheral sensory neurons and theintestinal tract, wherein the distribution pattern differs between thedifferent receptor classes.

Nociceptin acts at the molecular and cellular level in very much thesame way as opioids. However, its pharmacological effects sometimesdiffer from, and even oppose those of opioids. NOP-receptor activationtranslates into a complex pharmacology of pain modulation, which,depending on route of administration, pain model and species involved,leads to either pronociceptive or antinociceptive activity. Furthermore,the NOP receptor system is upregulated under conditions of chronic pain.Systemic administration of selective NOP receptor agonists was found toexert a potent and efficacious analgesia in non-human primate models ofacute and inflammatory pain in the absence of side effects. Theactivation of NOP receptors has been demonstrated to be devoid ofreinforcing effects but to inhibit opioid-mediated reward in rodents andnon-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171(16): 3777-3800, and references therein).

Besides the involvement of the NOP receptor in nociception, results frompreclinical experiments suggest that NOP receptor agonists might beuseful inter alia in the treatment of neuropsychiatric disorders (Witkinet al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al.,Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858). Remarkably, the DOPreceptor is also implicated to modulate not only pain but alsoneuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).

Strong opioids acting at the MOP receptor site are widely used to treatmoderate to severe acute and chronic pain. However, the therapeuticwindow of strong opioids is limited by severe side effects such asnausea and vomiting, constipation, dizziness, somnolence, respiratorydepression, physical dependence and abuse. Furthermore, it is known thatMOP receptor agonists show only reduced effectiveness under conditionsof chronic and neuropathic pain.

It is known that some of the above mentioned side-effects of strongopioids are mediated by activation of classic opioid-receptors withinthe central nervous system. Furthermore, peripheral opioid receptors,when activated, can inhibit transmission of nociceptive signals shown inboth, clinical and animal studies (Gupta et al., 2001; Kalso et al.,2002; Stein et al., 2003; Zollner et al., 2008).

Thus, to avoid CNS-mediated adverse effects after systemicadministration, one approach has been to provide peripherally restrictedopioid receptor ligands that do not easily cross the blood-brain barrierand therefore distribute poorly to the central nervous system (see forinstance WO 2015/192039). Such peripherally acting compounds mightcombine effective analgesia with limited side-effects.

Another approach has been to provide compounds which interact with boththe NOP receptor and the MOP receptor. Such compounds have for instancebeen described in WO 2004/043967, WO 2012/013343 and WO 2009/118168.

A further approach has been to provide multi-opioid receptor analgesicsthat modulate more than one of the opioid receptor subtypes to provideadditive or synergistic analgesia and/or reduced side effects like abuseliability or tolerance.

On the one hand, it would be desirable to provide analgesics thatselectively act on the NOP receptor system but less pronounced on theclassic opioid receptor system, especially MOP receptor system, whereasit would be desirable to distinguish between central nervous activityand peripheral nervous activity. On the other hand, it would bedesirable to provide analgesics that act on the NOP receptor system andalso to a balanced degree on the MOP receptor system, whereas it wouldbe desirable to distinguish between central nervous activity andperipheral nervous activity.

There is a need for medicaments which are effective in the treatment ofpain and which have advantages compared to the compounds of the priorart. Where possible, such medicaments should contain such a small doseof active ingredient that satisfactory pain therapy can be ensuredwithout the occurrence of intolerable treatment-emergent adverse events.

It is an object of the invention to provide pharmacologically activecompounds, preferably analgesics that have advantages compared to theprior art.

This object has been achieved by the subject-matter of the patentclaims.

A first aspect of the invention relates to3-((hetero-)aryl)-alkyl-8-amino-2-oxo-1,3-diaza-spiro-[4.5]-decanederivatives according to general formula (I)

whereinn means 1, 2 or 3;R¹ and R² independently of one another mean

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted; ora 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; orR¹ and R² together with the nitrogen atom to which they are attachedform a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I;preferably with the proviso that R¹ and R² do not simultaneously mean—H;R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted;R⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 6-14-memberedaryl moiety is optionally connected through —C(═O)—, —C(═O)O—,—C(═O)O—CH₂—, or —S(═O)₂—; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;R⁵ meansa 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; ora 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted;R⁷, R⁸, R¹¹, R¹², R¹³, R¹⁴, R⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted;or wherein R⁷ and R⁸ together with the carbon atom to which they areattached form a ring and mean —(CH₂)₂— or —(CH₂)₃—;wherein “mono- or polysubstituted” means that one or more hydrogen atomsare replaced by a substituent independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —R²¹, —C(═O)R²¹,C(═O)OR²¹, —C(═O)NR²¹R²², —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃,═O, —OR²¹, —OC(═O)R²¹, OC(═O)OR²¹, —OC(═O)N²¹R²², —NO₂, —NR²¹R²²,—NR²¹—(CH₂)₁₋₆—C(═O)R²², —NR²¹—(CH₂)₁₋₆—C(═O)OR²²,—NR²³—(CH₂)₁₋₆—C(═O)NR²¹R², —NR²¹C(═O)R²², —NR²¹C(═O)—OR²²,—NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —SR²¹, S(═O)R²¹, —S(═O)₂R²¹,—S(═O)₂OR²¹, and —S(═O)₂NR²¹R²²;whereinR²¹, R²² and R²³ independently of one another mean

—H;

—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, and —O—C₁-C₆-alkyl;a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted; wherein said 3-12-membered heterocycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;a 6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl;a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl;or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²², —NR²¹R²²,—NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², or —S(═O)₂NR²¹R²²together with the nitrogen atom to which they are attached form a ringand mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or (CH₂)₂—NR^(B)—(CH₂)₂—,wherein R^(B) means —H or —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br and —I;or a physiologically acceptable salt thereof.

Preferably, aryl includes but is not limited to phenyl and naphthyl.Preferably, heteroaryl includes but is not limited to -1,2-benzodioxole,-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl,-imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl,-benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl,-isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl,-benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or-1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but is notlimited to -cyclopropyl, -cyclobutyl, -cyclopentyl and -cyclohexyl.Preferably, heterocycloalkyl includes but is not limited to -aziridinyl,-azetidinyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl,-sulfamorpholinyl, -oxiridinyl, -oxetanyl, tetrahydropyranyl, and-pyranyl.

When a moiety is connected through an asymmetric group such as —C(═O)O—or —C(═O)O—CH₂—, said asymmetric group may be arranged in eitherdirection. For example, when R⁴ is connected to the core structurethrough —C(═O)O—, the arrangement may be either R⁴—C(═O)O-core orcore-C(═O)O—R⁴.

In preferred embodiments of the compound according to the invention, R⁷,R⁸, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ independentlyof one another mean —H, —F, —OH, or —C₁-C₆-alkyl; preferably —H.

In preferred embodiments of the compound according to the invention, R⁷and R⁸ together with the carbon atom to which they are attached form aring and mean —(CH₂)₂— (i.e. form a cyclopropyl ring) or —(CH₂)₃—(i.e.form a cyclobutyl ring).

In a preferred embodiment of the compound according to the invention, R¹means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R¹means —H and R² means —CH₃.

In another preferred embodiment of the compound according to theinvention, R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted.

Preferably, R¹ means —CH₃ and R² means —CH₃.

In still another preferred embodiment of the compound according to theinvention, R¹ and R² together with the nitrogen atom to which they areattached form a ring and mean —(CH₂)₃₋₆—. Preferably, R¹ and R² togetherwith the nitrogen atom to which they are attached form a ring and mean—(CH₂)₃—.

In yet another preferred embodiment,

-   -   R¹ means —H or —CH₃; and    -   R² means a 3-12-membered cycloalkyl moiety, saturated or        unsaturated, unsubstituted; wherein said 3-12-membered        cycloalkyl moiety is connected through —CH₂—, unsubstituted;        preferably —CH₂-cycloalkyl, —CH₂— cyclobutyl or        —CH₂-cyclopentyl; or R² means a 3-12-membered heterocycloalkyl        moiety, saturated or unsaturated, unsubstituted; wherein said        3-12-membered heterocycloalkyl moiety is connected through        —CH₂—, unsubstituted; preferably —CH₂-oxetanyl or        —CH₂-tetrahydrofuranyl.

In a preferred embodiment of the compound according to the invention, R³means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with —OCH₃.

In another preferred embodiment of the compound according to theinvention, R³ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted, optionally connected through —C₁-C₆-alkylene-, linearor branched, saturated or unsaturated, unsubstituted. In a preferredembodiment, R³ means -phenyl unsubstituted, mono- or polysubstituted.More preferably, R³ means -phenyl unsubstituted, mono- or disubstitutedwith —F, —Cl, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or —OCH₂OCH₃, preferably —F.In another preferred embodiment, R³ means -benzyl unsubstituted, mono-or polysubstituted. More preferably, R³ means -benzyl unsubstituted,mono- or disubstituted with —F, —Cl, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃ or—OCH₂OCH₃, preferably —F.

In still another preferred embodiment of the compound according to theinvention, R³ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted. Preferably, R³ means -thienyl or -pyridinyl,in each case unsubstituted, mono- or polysubstituted. More preferably,R³ means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in eachcase unsubstituted or monosubstituted with —F, —Cl or —CH₃.

In a preferred embodiment of the compound according to the invention, R⁴means —H.

In another preferred embodiment of the compound according to theinvention, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with a substituent selected from thegroup consisting of —F, —Cl, —Br, —I, —CN, —CF₃, —OH, —O—C₁-C₄-alkyl,—OCF₃, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —OC(═O)C₁-C₄-alkyl,—C(═O)C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁-C₄-alkyl, —C(═O)NHC₁-C₄-alkylene-CN,—C(═O)NHC₁-C₄-alkylene-O—C₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂;—S(═O)C₁-C₄-alkyl, and —S(═O)₂C₁-C₄-alkyl; or with —C(═O)NR²¹R²² whereinR²¹ and R²² together with the nitrogen atom to which they are attachedform a ring and mean —(CH₂)₃₋₆—, —(CH₂)₂—O—(CH₂)₂—, or—(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl; or with—C(═O)NH-3-12-membered cycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH; orwith —C(═O)NH-3-12-membered heterocycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH.More preferably, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or monosubstituted with —O—C₁-C₄-alkyl or—C(═O)N(C₁-C₄-alkyl)₂.

In still another preferred embodiment of the compound according to theinvention, R⁴ means a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein the3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R⁴ means a 3-12-membered cycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;wherein said 3-12-membered cycloalkyl moiety is connected through —CH₂—or —CH₂CH₂—. More preferably, R⁴ means a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl,—O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered cycloalkyl moiety isconnected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁴means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R⁴ means a 3-12-membered heterocycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered heterocycloalkyl moiety isconnected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means-oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl is connectedthrough —CH₂— or —CH₂CH₂—.

In yet another preferred embodiment of the compound according to theinvention, R⁴ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 6-14-membered aryl moiety is connectedthrough —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R⁴ means -phenyl,unsubstituted, mono- or polysubstituted; wherein said -phenyl isconnected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -phenyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid -phenyl is connected through —CH₂— or —CH₂CH₂—.

In a further preferred embodiment of the compound according to theinvention, R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis connected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said -phenyl is connected through —CH₂— or—CH₂CH₂—. More preferably, R⁴ means -pyridinyl, -pyrimidinyl,-pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,—C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said -pyridinyl, -pyrimidinyl, -pyrazinyl,or -pyrazolinyl is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, nmeans 1 or 2. Preferably, n means 1.

In a preferred embodiment of the compound according to the invention, R⁵means -phenyl, unsubstituted, mono- or polysubstituted. Preferably, R⁵means -phenyl unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F; —Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃;-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,mono- or polysubstituted; preferably -cyclopropyl, saturated,unsubstituted; -3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferably-pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl,-thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated,unsubstituted or monosubstituted with —C₁-C₄-alkyl; —O—CH₂—O— (such thatit is condensed with a dioxolanyl ring); —O—C₁-C₄-alkyl;—O—(CH₂CH₂—O)₁₋₃₀—H; —O—(CH₂CH₂—O)₁₋₃₀-CH₃; —C(═O)OH;—C(═O)OC₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl.

In another preferred embodiment of the compound according to theinvention, R⁵ means -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl,-thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each caseunsubstituted, mono- or polysubstituted. Preferably, R⁵ means-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl,-imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F;—Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃; —C₁-C₄-alkyl-OH;—C₁-C₄-alkyl-C(═O)NH₂; -3-12-membered cycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferably-cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably -pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl,-thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated,unsubstituted or monosubstituted with —C₁-C₄-alkyl; —O—CH₂—O— (such thatit is condensed with a dioxolanyl ring); —O—C₁-C₄-alkyl;—O—(CH₂CH₂—O)₁₋₃₀—H; —O—(CH₂CH₂—O)₁₋₃₀-CH₃; —C(═O)OH;—C(═O)OC₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —SC₁-C₄-alkyl; —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl.

In preferred embodiments, the compound according to the invention has astructure according to any of general formulas (II-A) to (VIII-C):

wherein in each caseR¹, R², R³, R⁴, and R⁵ are defined as above,R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; preferably —H or —OH;R^(D) means —H or —F;or a physiologically acceptable salt thereof.

Preferably, in the compounds according to general formula (I) or any ofthe compounds according to general formulas (II-A) to (VIII-C), R⁵ isselected from the group consisting of:

In a particularly preferred embodiment of the compound according to theinvention,

n means 1 or 2;R¹ means —H or —CH₃;R² means —H or —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or monosubstituted with —OH, —OCH₃,—C(═O)OCH₃, or —CN;R³ means—C₁-C₄-alkyl, optionally monosubstituted with —OCH₃;-phenyl, -thienyl or -pyridinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —CN, —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃, —O—CH₂—O—CH₃, —C(═O)NH₂,C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH,SOCH₃ and SO₂CH₃; orR⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,═O, —OH, —O—C₁-C₄-alkyl, —CO₂H, —C(═O)O—C₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NH—C₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —C(═O)NH—C₁-C₄-alkyl-CN,—C(═O)NCH₃—C₁-C₄-alkyl-CN, —C(═O)NH-cyclopropyl-CN,—C(═O)NCH₃-cyclopropyl-CN, —C(═O)NH—C₁-C₄-alkyl-OH,—C(═O)NCH₃—C₁-C₄-alkyl-OH, —C(═O)NH—C₁-C₄-alkyl-OCH₃,—C(═O)NCH₃—C₁-C₄-alkyl-OCH₃, —C(═O)NRR′ wherein R and R′ together withthe nitrogen atom to which they are attached form a ring and mean—(CH₂)₂₋₄—;3-6-membered cycloalkyl, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl,wherein said 3-6-membered cycloalkyl is connected through—C₁-C₆-alkylene;3-6-membered heterocycloalkyl, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —CN, —CO₂H,—C(═O)O—C₁-C₄-alkyl, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-memberedheterocycloalkyl is connected through —C₁-C₆-alkylene;6-14-membered aryl, unsubstituted or substituted with one, two, three orfour substituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —CO₂H, —C(═O)O—C₁-C₄-alkyl, —OH,and —O—C₁-C₄-alkyl; wherein said 6-14-membered aryl is connected through—C₁-C₆-alkylene- or —S(═O)₂—;5-14-membered heteroaryl, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —CO₂H,—C(═O)O—C₁-C₄-alkyl, —OH, and —O—C₁-C₄-alkyl; wherein said 5-14-memberedheteroaryl is connected through —C₁-C₆-alkylene- or —S(═O)₂—;R⁵ means -phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl,-thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F;—Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃; —C₁-C₄-alkyl-OH;—C₁-C₄-alkyl-C(═O)NH₂; -3-12-membered cycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferably-cyclopropyl, saturated, unsubstituted; -3-12-membered heterocycloalkyl,saturated or unsaturated, unsubstituted, mono- or polysubstituted;—O—CH₂—O—; —O—C₁-C₄-alkyl; —O—(CH₂CH₂—O)₁₋₃₀—H; —O—(CH₂CH₂—O)₁₋₃₀-CH₃;—C(═O)OH; —C(═O)OC₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —SC₁-C₄-alkyl; —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; andR⁷, R⁸, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.

In a particularly preferred embodiment of the compound according to theinvention,

n means 1 or 2; and/orR¹ means —H or —CH₃; and/orR² means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted;preferably, R² means —CH₃ or —CH₂CH₃; more preferably, R¹ and R² bothmean —CH₃; and/orR³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —CN, —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃,—C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, SOCH₃ andSO₂CH₃; preferably R³ means -phenyl, -thienyl or -pyridinyl, in eachcase unsubstituted or substituted with —F; more preferably, R³ meansphenyl, unsubstituted; and/orR⁴ means

—H;

—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, and —O—C₁-C₄-alkyl; or3-6-membered cycloalkyl, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl,wherein said 3-6-membered cycloalkyl is connected through—C₁-C₆-alkylene; preferably R⁴ means 3-6-membered cycloalkyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-memberedcycloalkyl is connected through —CH₂— or —CH₂CH₂—; more preferably, R⁴means -cyclobutyl, unsubstituted or monosubstituted with —OH, whereinsaid -cyclobutyl is connected through —CH₂—; and/orR⁵ means -phenyl, -pyridazinyl, -pyridinyl, or -pyrimidinyl, in eachcase unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F; —Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃;-3-12-membered cycloalkyl, saturated or unsaturated, unsubstituted,mono- or polysubstituted; preferably -cyclopropyl, saturated,unsubstituted; -3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferably-pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl,-thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated,unsubstituted or monosubstituted with —C₁-C₄-alkyl; —O—CH₂—O— (such thatit is condensed with a dioxolanyl ring); —O—C₁-C₄-alkyl;—O—(CH₂CH₂—O)₁₋₃₀—H; —O—(CH₂CH₂—O)₁₋₃₀-CH₃; —C(═O)OH;—C(═O)OC₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; and/orR⁷, R⁸, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ mean —H.

In preferred embodiments, the compound according to the invention isselected from the group consisting of

SC_2001CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2002CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2003CIS-8-Dimethylamino-1-isopropyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2004CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2005CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-[methyl-(2-methyl-propyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2006CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2007CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyrazin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2008CIS-8-(Allyl-methyl-amino)-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2009CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2010CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2011CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2012CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2013CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2014CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2015CIS-1-Butyl-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2016CIS-8-Dimethylamino-8-(4-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2017CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2018CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2019CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2020CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[3-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2021CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one hydrochloride SC_2022CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2023CIS-1-(Cyclopentyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2024CIS-8-Dimethylamino-1-(2-hydroxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2025CIS-8-Dimethylamino-1-(2-methoxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2026CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2027CIS-3-[[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2028CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-(methyl-propyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2029CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2030CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionitrile SC_2031CIS-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2032CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(oxetan-3-yl-methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2033CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2034CIS-8-Dimethylamino-1-(2-hydroxy-ethyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2035CIS-8-Dimethylamino-1-(2,2-dimethyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2036CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methyl-butyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2037CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-[3-(trifluoromethyloxy)-propyl]-1,3-diazaspiro[4.5]decan-2-one SC_2038CIS-1-(2-Cyclobutyl-ethyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2039CIS-1-[(3,3-Difluoro-cyclobutyl)-methyl]-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2040CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-acetonitrile SC_2041CIS-1-(Cyclobutyl-methyl)-8-[(2-methoxy-ethyl)-methyl-amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2042CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid tert-butyl ester SC_2043CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid; 2,2,2-trifluoro-acetic acid saltSC_2044CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2045CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid methyl ester SC_2046CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide SC_2047CIS-1-Benzyl-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2048CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-acetamide SC_2049CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide SC_2050CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methoxy-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2051CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2052CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2053CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetonitrile SC_2054CIS-8-Dimethylamino-1-hexyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2055CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2056CIS-1-(Cyclohexyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2057CIS-N-(Cyano-methyl)-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide SC_2058CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2059CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3-methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-one SC_2060CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-(2-methoxy-ethyl)-acetamide SC_2062CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2063CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide SC_2064CIS-N-(1-Cyano-cyclopropyl)-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide SC_2065CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-N-propyl-acetamide SC_2066CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3-methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-one SC_2067CIS-8-Dimethylamino-1-(3-hydroxy-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2068CIS-8-Dimethylamino-1-(4-methoxy-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2069CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2070CIS-8-Dimethylamino-1-[(1-hydroxy-cyclohexyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2071CIS-5-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-pentanenitrile SC_2072CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionamide SC_2073CIS-1-(Cyclobutyl-methyl)-8-[(2-hydroxy-ethyl)-methyl-amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2074CIS-1-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-cyclobutane-1-carbonitrile SC_2075CIS-8-Dimethylamino-1-[(1-hydroxy-cyclopentyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2076CIS-3-[(2-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2077CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-propionamide SC_2078CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-propionamide SC_2079CIS-8-Dimethylamino-1-[(1-fluoro-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2080CIS-1-(2-Cyclohexyl-ethyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2081CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2082CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-methyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2083CIS-8-Dimethylamino-1-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2084CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(2-tetrahydro-pyran-4-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one SC_2085CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2086CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[[6-(trifluoromethyl)-pyridin-3-yl]-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2087CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[4-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2088CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2089CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2090CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2091CIS-8-Dimethylamino-1-[(1-methoxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2092CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2093CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2094CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2095CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one SC_2096CIS-3-Benzyl-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2097CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2099CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(pyrimidin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2100CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-2,2-dimethyl-propionitrile SC_2101CIS-2-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-benzoic acid methyl ester SC_2102CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2103CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2104CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2105CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyrimidin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2106CIS-3-[[1-[(5-Cyano-2-methoxy-phenyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-4-methoxy-benzonitrile SC_2107CIS-8-Dimethylamino-1-(3-hydroxy-3-methyl-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2108CIS-8-Dimethylamino-1-(3-methoxy-3-methyl-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2109CIS-2-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2110CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2111CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2112CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2113CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-furan-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2114CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2115CIS-3-Benzyl-8-dimethylamino-1-ethyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2117CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[2-(methylsulfinyl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2118CIS-8-Dimethylamino-1-[(2R)-2-hydroxy-propyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2119CIS-8-Dimethylamino-1-[(2S)-2-hydroxy-propyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2120CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2122CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2123CIS-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2124CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one SC_2125CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2126CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-4-methoxy-benzonitrile SC_2127CIS-8-Dimethylamino-1-ethyl-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2129CIS-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2130CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2131CIS-8-Dimethylamino-8-[4-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2132CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid SC_2133CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid tert-butyl ester SC_2134CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-acetic acid methyl esterSC_2135CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methyl-but-2-enyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2136CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfanyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2137CIS-3-[(3-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2138CIS-2-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile SC_2139CIS-8-Dimethylamino-8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2140CIS-8-Dimethylamino-8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2141CIS-3-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile SC_2142CIS-3-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-4-methoxybenzonitrile SC_2143CIS-8-Dimethylamino-8-phenyl-3-(1H-[1,2,3]triazol-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2144CIS-8-Dimethylamino-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2145CIS-2-[4-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide SC_2146CIS-8-Methylamino-8-phenyl-3-(1H-[1,2,3]triazol-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2147CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one SC_2148CIS-2-[4-[(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide SC_2149CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decane-1-carboxylic acid benzyl ester SC_2150CIS-3-[[1-(2-Hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2152CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2153CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2155CIS-2-[4-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3]triazol-1-yl]-acetamideSC_2156CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2159CIS-2-[4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide SC_2160CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2161CIS-2-[4-[[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3]triazol-1-yl]-acetamideSC_2162CIS-1-(Cyclobutyl-methyl)-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2163CIS-2-[4-[[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide SC_2164CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2165CIS-8-Dimethylamino-3-[2-(1H-imidazol-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2166CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2167CIS-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-2-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2168CIS-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2169CIS-8-Dimethylamino-1-ethyl-3-[(4-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2170CIS-8-Dimethylamino-3-(1-methyl-1-phenyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2171CIS-8-Dimethylamino-8-phenyl-3-(1-phenyl-cyclopropyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2172CIS-8-Dimethylamino-1,3-bis[(2-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2173CIS-8-Dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2174CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(1-methyl-1-phenyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2175CIS-3-[(3-Cyclopropyl-phenyl)-methyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2176CIS-3-(1,3-Benzodioxol-4-yl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2177CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(1-phenyl-cyclopropyl)-1,3-diazaspiro[4.5]decan-2-one SC_2178CIS-4-[[8-Dimethylamino-3-[(2-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-benzonitrile SC_2179CIS-8-Dimethylamino-3-[(2-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2180CIS-8-Dimethylamino-8-phenyl-3-(pyridin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2181CIS-8-Dimethylamino-8-phenyl-3-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2182CIS-8-Dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2183CIS-8-Dimethylamino-3-[[2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2184CIS-8-Dimethylamino-8-phenyl-3-[(2-piperidin-1-yl-pyridin-4-yl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2185CIS-8-Dimethylamino-3-[(2-morpholin-4-yl-pyridin-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2186CIS-8-Dimethylamino-8-phenyl-3-[(2-piperazin-1-yl-pyridin-4-yl)-methyl]-1,3-diazaspiro[4.5]decan-2-oneand the physiologically acceptable salts thereof.

According to the invention, unless expressly stated otherwise,“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can belinear or branched, saturated or unsaturated. Linear saturated alkylincludes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.Examples of branched saturated alkyl include but are not limited toiso-propyl, sec-butyl, and tert-butyl. Examples of linear unsaturatedalkyl include but are not limited to vinyl, propenyl, allyl, andpropargyl.

According to the invention, unless expressly stated otherwise,“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can beunsubstituted, mono- or polysubstituted. Examples of substituted alkylinclude but are not limited to —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—CH₂CH₂S(═O)₂CH₃, —CH₂C(═O)NH₂, —C(CH₃)₂C(═O)NH₂, —CH₂C(CH₃)₂C(═O)NH₂,and —CH₂CH₂C(═O)N(CH₃)₂.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of saturatedalkylene include but are not limited to —CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)—CH(CH₃)—, —C(CH₃)₂CH₂—,—CH₂C(CH₃)₂—, —CH(CH₃)C(CH₃)₂—, —C(CH₃)₂CH(CH₃)—, C(CH₃)₂C(CH₃)₂—,—CH₂CH₂CH₂—, and —C(CH₃)₂CH₂CH₂—. Examples of unsaturated alkyleneinclude but are not limited to —CH═CH—, —C≡C—, —C(CH₃)═CH—, —CH═C(CH₃)—,—C(CH₃)═C(CH₃)—, —CH₂CH═CH—, —CH═CHCH₂—, —CH═CH—CH═CH—, and —CH═CH—C≡C—.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of substituted—C₁-C₆-alkylene- include but are not limited to —CHF—, —CF₂—, —CHOH— and—C(═O)—.

According to the invention, moieties may be connected through—C₁-C₆-alkylene-, i.e. the moieties may not be directly bound to thecore structure of compound according to general formula (I), but may beconnected to the core structure of compound according to general formula(I) or its periphery through a —C₁-C₆-alkylene-linker.

According to the invention, “3-12-membered cycloalkyl moiety” means anon-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to12 ring carbon atoms but no heteroatoms in the ring. Examples ofpreferred saturated 3-12-membered cycloalkyl moieties according to theinvention include but are not limited to cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, anddecaline. Examples of preferred unsaturated 3-12-membered cycloalkylmoiety moieties according to the invention include but are not limitedto cyclopropene, cyclobutene, cyclopentene, cyclopentadiene,cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene. The3-12-membered cycloalkyl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 6-14-memberedaryl moiety, unsubstituted, mono- or polysubstituted; and/or with a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 3-12-membered heterocycloalkyl moieties includebut are not limited to octahydro-1H-indol, decahydroquinoline,decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, anddecahydroquinoxalin, which in each case are connected through the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 6-14-membered aryl moieties include but are notlimited to 2,3-dihydro-1H-indene and tetraline, which in each case areconnected through the 3-12-membered cycloalkyl moiety. Examples of3-12-membered cycloalkyl moieties condensed with 5-14-memberedheteroaryl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 3-12-membered cycloalkyl moiety.

According to the invention, the 3-12-membered cycloalkyl moiety mayoptionally be connected through —C₁-C₆-alkylene-, i.e. the 3-12-memberedcycloalkyl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene-linker. Examples include but are not limited to—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, and—CH₂CH₂-cyclohexyl.

According to the invention, unless expressly stated otherwise, the3-12-membered cycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered cycloalkylmoieties include but are not limited to —CH₂-1-hydroxy-cyclobutyl.

According to the invention, “3-12-membered heterocycloalkyl moiety”means a non-aromatic, monocyclic, bicyclic or tricyclic moietycomprising 3 to 12 ring atoms, wherein each cycle comprisesindependently of one another 1, 2, 3, 4 or more heteroatomsindependently of one another selected from the group consisting ofnitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S(═O) or(S(═O)₂), whereas the remaining ring atoms are carbon atoms, and whereasbicyclic or tricyclic systems may share common heteroatom(s). Examplesof preferred saturated 3-12-membered heterocycloalkyl moieties accordingto the invention include but are not limited to aziridin, azetidine,pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine,triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane,tetrahydropyrane, thiirane, thietane, tetrahydrothiophene, diazepane,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,thiadiazolidine, morpholine, thiomorpholine. Examples of preferredunsaturated 3-12-membered heterocycloalkyl moiety moieties according tothe invention include but are not limited to oxazoline, pyrazoline,imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran.The 3-12-membered heterocycloalkyl moiety, which is bonded to thecompound according to the invention, in its periphery may optionally becondensed with a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; and/or with a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered heterocycloalkyl moieties. Examples of 3-12-memberedheterocycloalkyl moieties condensed with 3-12-membered cycloalkylmoieties include but are not limited to octahydro-1H-indol,decahydroquinoline, decahydroisoquinoline,octahydro-2H-benzo[b][1,4]-oxazin, and decahydroquinoxalin, which ineach case are connected through the 3-12-membered heterocycloalkylmoiety. An examples of a 3-12-membered heterocycloalkyl moiety condensedwith a 6-14-membered aryl moiety includes but is not limited to1,2,3,4-tetrahydroquinoline, which is connected through the3-12-membered heterocycloalkyl moiety. An example of a 3-12-memberedheterocycloalkyl moiety condensed with a 5-14-membered heteroarylmoieties includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 3-12-membered heterocycloalkyl moiety.

According to the invention, the 3-12-membered heterocycloalkyl moietymay optionally be connected through —C₁-C₆-alkylene-, i.e. the3-12-membered heterocycloalkyl moiety may not be directly bound to thecompound according to general formula (I) but may be connected theretothrough a —C₁-C₆-alkylene-linker. Said linker may be connected to acarbon ring atom or to a hetero ring atom of the 3-12-memberedheterocycloalkyl moiety. Examples include but are not limited to—CH₂-oxetane, —CH₂-pyrrolidine, —CH₂-piperidine, —CH₂-morpholine,—CH₂CH₂-oxetane, —CH₂CH₂-pyrrolidine, —CH₂CH₂-piperidine, and—CH₂CH₂-morpholine.

According to the invention, unless expressly stated otherwise, the3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered heterocycloalkylmoieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-,3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl,3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl,-tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.

According to the invention, “6-14-membered aryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring carbon atoms but no heteroatoms in the ring. Examples of preferred6-14-membered aryl moieties according to the invention include but arenot limited to benzene, naphthalene, anthracen, and phenanthren. The6-14-membered aryl moiety, which is bonded to the compound according tothe invention, in its periphery may optionally be condensed with a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 6-14-membered aryl moieties condensed with 3-12-memberedcycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indeneand tetraline, which in each case are connected through the6-14-membered aryl moiety. An example of a 6-14-membered aryl moietycondensed with a 3-12-membered heterocycloalkyl moiety includes but isnot limited to 1,2,3,4-tetrahydroquinoline, which is connected throughthe 6-14-membered aryl moiety. Examples of 6-14-membered aryl moietiescondensed with 5-14-membered heteroaryl moieties include but are notlimited to quinoline, isoquinoline, phenazine and phenoxacine, which ineach case are connected through the 6-14-membered aryl moiety.

According to the invention, the 6-14-membered aryl moiety may optionallybe connected through —C₁-C₆-alkylene-, i.e. the 6-14-membered arylmoiety may not be directly bound to the compound according to generalformula (I) but may be connected thereto through a—C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ringatom or to a hetero ring atom of the 6-14-membered aryl moiety. Examplesinclude but are not limited to —CH₂—C₆H₅, —CH₂CH₂—C₆H₅ and —CH═CH—C₆H₅.

According to the invention, unless expressly stated otherwise, the6-14-membered aryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 6-14-membered aryl moietiesinclude but are not limited to 2-fluorophenyl, 3-fluorophenyl,2-methoxyphenyl and 3-methoxyphenyl.

According to the invention, “5-14-membered heteroaryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring atoms, wherein each cycle comprises independently of one another 1,2, 3, 4 or more heteroatoms independently of one another selected fromthe group consisting of nitrogen, oxygen and sulfur, whereas theremaining ring atoms are carbon atoms, and whereas bicyclic or tricyclicsystems may share common heteroatom(s). Examples of preferred5-14-membered heteroaryl moieties according to the invention include butare not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole,furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine,pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine,1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine. The5-14-membered heteroaryl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 5-14-membered heteroaryl moieties condensed with3-12-membered cycloalkyl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 5-14-membered heteroaryl moiety. Anexamples of a 5-14-membered heteroaryl moiety condensed with a3-12-membered heterocycloalkyl moiety includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 5-14-membered heteroaryl moiety. Examples of 5-14-memberedheteroaryl moieties condensed with 6-14-membered aryl moieties includebut are not limited to quinoline, isoquinoline, phenazine andphenoxacine, which in each case are connected through the 5-14-memberedheteroaryl moiety.

According to the invention, the 5-14-membered heteroaryl moiety mayoptionally be connected through —C₁-C₆-alkylene-, i.e. the 5-14-memberedheteroaryl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ringatom or to a hetero ring atom of the 5-14-membered heteroaryl moiety.Examples include but are not limited to —CH₂-oxazole, —CH₂-isoxazole,—CH₂-imidazole, —CH₂-pyridine, —CH₂-pyrimidine, —CH₂-pyridazine,—CH₂CH₂-oxazole, —CH₂CH₂-isoxazole, —CH₂CH₂-imidazole, —CH₂CH₂-pyridine,—CH₂CH₂-pyrimidine, and —CH₂CH₂-pyridazine.

According to the invention, unless expressly stated otherwise, the5-14-membered heteroaryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of 5-14-membered heteroaryl moieties includebut are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl,3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl,2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl,3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl,4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl, and2-methoxy-6-pyrazinyl.

Preferably, the compounds according to the invention have a structureaccording to general formula (I′)

wherein R¹ to R⁵, R⁷, R⁸, R¹⁰ to R²⁰ and n are defined as above, or aphysiologically acceptable salt thereof.

In one preferred embodiment, the excess of the cis-isomer so designatedis at least 50% de, more preferably at least 75% de, yet more preferablyat least 90% de, most preferably at least 95% de and in particular atleast 99% de.

In a preferred embodiment, the compound according to the invention has astructure according to general formula (IX)

whereinR^(C) means —H or —OH;R³ means -phenyl or -3-fluorophenyl; andR⁵ means6-14-membered aryl, unsubstituted, mono- or polysubstituted; or5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted;or a physiologically acceptable salt thereof.

Preferably, R⁵ is selected from -phenyl, -pyridyl, pyrimidinyl, or-triazolyl, in each case unsubstituted, mono- or polysubstituted.

In a preferred embodiment, the compounds according to the invention arein the form of the free bases.

In another preferred embodiment, the compounds according to theinvention are in the form of the physiologically acceptable salts.

For the purposes of the description, a “salt” is to be understood asbeing any form of the compound in which it assumes an ionic form or ischarged and is coupled with a counter-ion (a cation or anion) or is insolution. The term is also to be understood as meaning complexes of thecompound with other molecules and ions, in particular complexes whichare associated via ionic interactions. Preferred salts arephysiologically acceptable, in particular physiologically acceptablesalts with anions or acids or also a salt formed with a physiologicallyacceptable acid.

Physiologically acceptable salts with anions or acids are salts of theparticular compound in question with inorganic or organic acids whichare physiologically acceptable, in particular when used in humans and/ormammals. Examples of physiologically acceptable salts of particularacids include but are not limited to salts of hydrochloric acid,sulfuric acid, and acetic acid.

The invention also includes isotopic isomers of a compound according tothe invention, wherein at least one atom of the compound is replaced byan isotope of the respective atom which is different from the naturallypredominantly occurring isotope, as well as any mixtures of isotopicisomers of such a compound. Preferred isotopes are ²H (deuterium), ³H(tritium), ¹³C and ¹⁴C.

Certain compounds according to the invention are useful for modulating apharmacodynamic response from one or more opioid receptors (mu, delta,kappa, NOP/ORL-1) either centrally or peripherally, or both. Thepharmacodynamic response may be attributed to the compound eitherstimulating (agonizing) or inhibiting (antagonizing) the one or morereceptors. Certain compounds according to the invention may antagonizeone opioid receptor, while also agonizing one or more other receptors.Compounds according to the invention having agonist activity may beeither full agonists or partial agonists.

As used herein, compounds that bind to receptors and mimic theregulatory effects of endogenous ligands are defined as “agonists”.Compounds that bind to a receptor but produce no regulatory effect, butrather block the binding of ligands to the receptor, are defined as“antagonists”.

In certain embodiments, the compounds according to the invention areagonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or deltaopioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.

The compounds according to the invention potently bind to the MOP and/orKOP and/or DOP and/or NOP receptors.

The compounds according to the invention can be modulators at the MOPand/or KOP and/or DOP and/or NOP receptors, and therefore the compoundsaccording to the invention can be used/administered to treat,ameliorate, or prevent pain.

In some embodiments, the compounds according to the invention areagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are agonists of the MOP and/or KOPand/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention areantagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are antagonists of the MOP and/orKOP and/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor; and (ii) agonist activity atone or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor; and (ii) antagonist activityat one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor; and (ii) agonist activityat one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor; and (ii) antagonistactivity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the NOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the MOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        DOP receptor;    -   can be regarded as opioid pan agonists, i.e. have agonist        activity at the NOP receptor as well as agonist activity at the        MOP receptor as well as agonist activity at the KOP receptor as        well as agonist activity at the DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        DOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the KOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        DOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the KOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the NOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveagonist activity at the MOP receptor, agonist activity at the KOPreceptor, and antagonist activity at the DOP receptor. In someembodiments, preferably with respect to receptors of the peripheralnervous system, the compounds according to the invention

-   -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor;    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as agonist activity at the NOP        receptor;    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as antagonist activity at the NOP        receptor; or    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor, no significant activity at the NOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveantagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have antagonistactivity at the NOP receptor as well as agonist activity at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe central nervous system, the compounds according to the invention

-   -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor;    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor;    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor; or    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

For the purpose of the specification, “no significant activity” meansthat the activity (agonist/antagonist) of the given compound at thisreceptor is lower by a factor of 1000 or more compared to its activity(agonist/antagonist) at one or more of the other opioid receptors.

A further aspect of the invention relates to the compounds according tothe invention as medicaments.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of pain. A further aspect of theinvention relates to a method of treating pain comprising theadministration of a pain alleviating amount of a compound according tothe invention to a subject in need thereof, preferably to a human. Thepain is preferably acute or chronic. The pain is preferably nociceptiveor neuropathic.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of neurodegenerative disorders,neuroinflammatory disorders, neuropsychiatric disorders, and substanceabuse/dependence. A further aspect of the invention relates to a methodof treating any one of the aforementioned disorders, diseases orconditions comprising the administration of a therapeutically effectiveamount of a compound according to the invention to a subject in needthereof, preferably to a human.

Another aspect of the invention relates to a pharmaceutical compositionwhich contains a physiologically acceptable carrier and at least onecompound according to the invention.

Preferably, the composition according to the invention is solid, liquidor pasty; and/or contains the compound according to the invention in anamount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, basedon the total weight of the composition.

The pharmaceutical composition according to the invention can optionallycontain suitable additives and/or auxiliary substances and/or optionallyfurther active ingredients.

Examples of suitable physiologically acceptable carriers, additivesand/or auxiliary substances are fillers, solvents, diluents, coloringsand/or binders. These substances are known to the person skilled in theart (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetikand angrenzende Gebiete, Editio Cantor Aulendoff).

The pharmaceutical composition according to the invention contains thecompound according to the invention in an amount of preferably from0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet morepreferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. %and in particular from 2.5 to 60 wt. %, based on the total weight of thepharmaceutical composition.

The pharmaceutical composition according to the invention is preferablyfor systemic, topical or local administration, preferably for oraladministration.

Another aspect of the invention relates to a pharmaceutical dosage formwhich contains the pharmaceutical composition according to theinvention.

In one preferred embodiment, the pharmaceutical dosage form according tothe invention is produced for administration twice daily, foradministration once daily or for administration less frequently thanonce daily. Administration is preferably systemic, in particular oral.

The pharmaceutical dosage form according to the invention can beadministered, for example, as a liquid dosage form in the form ofinjection solutions, drops or juices, or as a semi-solid dosage form inthe form of granules, tablets, pellets, patches, capsules,plasters/spray-on plasters or aerosols. The choice of auxiliarysubstances etc. and the amounts thereof to be used depend on whether theform of administration is to be administered orally, perorally,parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or locally, forexample to the skin, the mucosa or into the eyes.

Pharmaceutical dosage forms in the form of tablets, dragees, capsules,granules, drops, juices and syrups are suitable for oral administration,and solutions, suspensions, readily reconstitutable dry preparations andalso sprays are suitable for parenteral, topical and inhalatoryadministration. Compounds according to the invention in a depot, indissolved form or in a plaster, optionally with the addition of agentspromoting penetration through the skin, are suitable percutaneousadministration preparations.

The amount of the compounds according to the invention to beadministered to the patient varies in dependence on the weight of thepatient, on the type of administration, on the indication and on theseverity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg,preferably from 0.001 mg/kg to 10 mg/kg, of at least one compoundaccording to the invention is administered.

Another aspect of the invention relates to a process for the preparationof the compounds according to the invention. Suitable processes for thesynthesis of the compounds according to the invention are known inprinciple to the person skilled in the art.

Preferred synthesis routes are described below:

The compounds according to the invention can be obtained via differentsynthesis routes. Depending on the synthesis route, differentintermediates are prepared and subsequently further reacted.

In a preferred embodiment, the synthesis of the compounds according tothe invention proceeds via a synthesis route which comprises thepreparation of an intermediate according to general formula (IIIa):

wherein R¹, R² and R³ are defined as above.

In another preferred embodiment, the synthesis of the compoundsaccording to the invention proceeds via a synthesis route whichcomprises the preparation of an intermediate according to generalformula (IIIb):

wherein R¹, R² and R³ are defined as above and PG is a protecting group.

Preferably the protecting group is -p-methoxybenzyl. Therefore, inanother preferred embodiment, the synthesis of the compounds accordingto the invention proceeds via a synthesis route which comprises thepreparation of an intermediate according to general formula (IIIc):

wherein R¹, R² and R³ are defined as above.

As already indicated, in general formula (IIIc), the -p-methoxybenzylmoiety represents a protecting group which can be cleaved in the courseof the synthesis route.

In yet another preferred embodiment, the synthesis of the compoundsaccording to the invention proceeds via a synthesis route whichcomprises the preparation of

-   -   an intermediate according to general formula (IIIa) and        according to general formula (IIIb); or    -   an intermediate according to general formula (IIIa) and        according to general formula (IIIc); or    -   an intermediate according to general formula (IIIb) and        according to general formula (IIIc); or    -   an intermediate according to general formula (IIIa), according        to general formula (IIIb) and according to general formula        (IIIc).

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

EXAMPLES

“RT” means room temperature (23±7° C.), “M” are indications ofconcentration in mol/l, “aq.” means aqueous, “sat.” means saturated,“sol.” means solution, “conc.” means concentrated.

Further abbreviations:

-   brine saturated aqueous sodium chloride solution-   CC column chromatography-   cHex cyclohexane-   DCM dichloromethane-   DIPEA N,N-diisopropylethylamine-   DMF N,N-dimethylformamide-   Et Ethyl-   ether diethyl ether-   EE ethyl acetate-   EtOAc ethyl acetate-   EtOH ethanol-   h hour(s)-   H₂O water-   HATU    O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   LDA Lithium-di-isoproyl-amid-   Me Methyl-   m/z mass-to-charge ratio-   MeOH methanol-   MeCN acetonitrile-   min minutes-   MS mass spectrometry-   NBS N-bromo-succinimide-   NEt₃ triethylamine-   PE Petrol Ether (60-80° C.)-   RM reaction mixture-   RT room temperature-   T3P    2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide-   tBME tert-.butyl methyl ether-   THF tetrahydrofuran-   v/v volume to volume-   w/w weight to weight

The yields of the compounds prepared were not optimised. Alltemperatures are uncorrected.

All starting materials, which are not explicitly described, were eithercommercially available (the details of suppliers such as for exampleAcros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge,Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® AvailableChemicals Database of MDL, San Ramon, US or the SciFinder® Database ofthe ACS, Washington D.C., US, respectively, for example) or thesynthesis thereof has already been described precisely in the specialistliterature (experimental guidelines can be found in the Reaxys® Databaseof Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS,Washington D.C., US, repspectively, for example) or can be preparedusing the conventional methods known to the person skilled in the art.

The mixing ratios of solvents or eluents for chromatography arespecified in v/v.

All the intermediate products and exemplary compounds were analyticallycharacterised by mass spectrometry (MS, m/z for [M+H]⁺). In addition¹H-NMR and ¹³C spectroscopy was carried out for all the exemplarycompounds and selected intermediate products.

Remark Regarding Stereochemistry

CIS refers to the relative configuration of compounds described herein,in which both nitrogen atoms are drawn on the same face of thecyclohexane ring as described in the following exemplary structure. Twodepictions are possible:

TRANS refers to compounds, in which both nitrogen atoms are on oppositefaces of the cyclohexane ring as described in the following exemplarystructure. Two depictions are possible:

Synthesis of Intermediates Synthesis of INT-795:CIS-8-Dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione

A diastereomeric mixture of8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (20 g)(INT-976 step 1) was suspended in methanol (200 mL) and was heated to80° C. for 1 h. The resulting suspension was filtered hot and theprecipitate was washed with methanol (100 mL). Solid obtained was driedunder reduced pressure to afford major isomerCIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (15g) as an off-white solid. Chiral HPLC purity 98.93%, HPLC purity 98.61%.

Step 2:CIS-8-Dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione

Cs₂CO₃ (3.9 g, 10.98 mmol) was added to the solution ofCIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.5g, 5.49 mmol) in MeCN (20 mL) under argon atmosphere and the reactionmixture was stirred for 30 min. (2-Bromoethyl)benzene (1.5 g, 8.24 mmol)was added and the reaction mixture was stirred under reflux for 16 h.The reaction completion was monitored by TLC. The reaction mixture wasquenched with water (25 mL) and the organic product was extracted withDCM (2×150 mL). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo. Purification of the residue by flashcolumn chromatography on silica gel (230-400 mesh) (5-10% methanol inDCM) further by washing with pentane yielded 1.6 g (78%) ofCIS-8-dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dioneas white solid. (TLC system: 10% MeOH in DCM; Rf: 0.4).

Step 3:CIS-8-Dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one

Anhydrous AlCl₃ (1.27 g, 9.59 mmol) was added to the solution of LiAlH₄(1M in THF) (7.6 mL, 7.67 mmol) in THF at 0° C. under argon atmosphere.The reaction was stirred at RT for 1 h.CIS-8-(Dimethylamino)-3-phenethyl-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione(1.5 g, 4.60 mmol) was added to the reaction mixture at 0° C. andstirred at RT for 16 h. The reaction completion was monitored by TLC.The mixture was cooled to 0° C.; quenched with sat. aq. Na₂SO₄ (10 mL)and filtered through celite. The filtrate was dried over anhydrousNa₂SO₄ and concentrated in vacuo. Purification of the residue by flashcolumn chromatography on silica gel (230-400 mesh) (5-10% methanol inDCM) and further by washing with pentane yielded 1 g (69%) ofCIS-8-dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one(INT-795) as a white solid. (TLC system: 10% MeOH in DCM; Rf: 0.3).[M+H]⁺ 378.

Synthesis of INT-799:CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaOH (1.42 g, 35.5 mmol) was added to a solution ofCIS-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-794) (3 g, 7.09 mmol) in DMSO (90 mL) under argon atmosphere andthe reaction mixture was stirred at 80° C. for 30 min.((1-(Bromomethyl)cyclobutoxy)methyl)benzene (5.4 g, 21.3 mmol) was addedand stirring was continued for 2 days at 80° C. The reaction completionwas monitored by TLC. The reaction mixture was diluted with water (500mL) and extracted with diethyl ether (4×300 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (230-400mesh silica gel; 65-70% EtOAc in petroleum ether as eluent) to afford2.5 g (59%) ofCIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(TLC system: 10% MeOH in DCM; Rf: 0.8).

Step 2:CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

TFA (12 mL) was added toCIS-1-((1-(benzyloxy)cyclobutyl)methyl)-3-(3,4-dimethoxybenzyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(2.5 g, 4.18 mmol) at 0° C. and the resulting mixture was stirred at 70°C. for 6 h. The reaction completion was monitored by LCMS. The reactionmixture was concentrated under reduced pressure. To the residue sat. aq.NaHCO₃ was added (until pH 10) and the organic product was extractedwith DCM (3×150 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by column chromatography (230-400 mesh silica gel; 5% MeOHin DCM as eluent) to afford 500 mg (33%) ofCIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-799) (TLC system: 10% MeOH in DCM; Rf: 0.5). [M+H]⁺ 358.2

Synthesis of INT-951:CIS-1-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile

Step 1:1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

NaH (50% in mineral oil) (2.44 g, 50.89 mmol) was added to a solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (5 g, 12.72 mmol) in DMF (100 mL) at 0° C. portionwise over 10min. 1-(Bromomethyl)cyclobutanecarbonitrile (4.4 g, 25.44 mmol) wasadded dropwise over 10 minutes at 0° C. The reaction mixture was allowedto stir at RT for 3 h, then quenched with water and the organic productwas extracted with ethyl acetate (3×200 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 5 g (crude) of1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutane-carbonitrileas gummy brown liquid. The material was used for the next step withoutfurther purification.

Step 2:1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide

TFA (100 mL) was added to1-((CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile(5 g, 10.28 mmol) at 0° C. and the reaction mixture at mixture wasstirred at RT for 2 days. The reaction mixture was concentrated invacuo. To the residue sat. aq. NaHCO₃ was added (until pH 10) and theorganic product was extracted with dichloromethane (3×150 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 3.5 g (crude) of1-((CIS-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide. The material was used for the next step withoutfurther purification.

Step 3:1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarbonitrile

Thionyl chloride (35 mL) was added to1-((cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)methyl)cyclobutanecarboxamide(3.5 g, 9.11 mmol) at RT and the resulting mixture was stirred at refluxfor 2 h. The reaction mixture was concentrated in vacuo. To the residuesat. aq. NaHCO₃ was added (until pH 10) and the organic product wasextracted with dichloromethane (3×150 mL). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by column chromatography to afford 1.3 g (34% after threesteps) ofCIS-1-[(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-methyl]-cyclobutane-1-carbonitrile(INT-951). [M+H]⁺ 367.2.

Synthesis of INT-953:CIS-1-(Cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one

To a stirred solution of3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(4 g, 12.04 mmol) in anhydrous DMF (60 ml) was added NaH (1.38 g, 60%dispersion in oil, 36.14 mmol) at RT. The reaction mixture was stirredfor 10 min, bromomethylcyclobutane (3 ml, 26.5 mmol) was added dropwiseand stirring was continued for 50 h. TLC analysis showed completeconsumption of the starting material. The reaction mixture was quenchedwith sat. aq. NH₄Cl (50 ml) and extracted with EtOAc (3×200 ml). Thecombined organic phase was dried over Na₂SO₄ and concentrated underreduced pressure. The resulting residue was purified columnchromatography (neutral aluminum oxide, EtOAc— petroleum ether (2:8)) togive1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(2.4 g, 50%, white solid). TLC system: EtOAc—pet ether (6:4);R_(f)=0.48.

Step 2:1-Cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione

To a stirred solution of1-cyclobutylmethyl-3-(4-methoxy-benzyl)-9,12-dioxa-1,3-diaza-dispiro[4.2.4.2]tetradecan-2-one(1 g, 2.5 mmol) in MeOH (7 ml) was added 10% aq. HCl (8 ml) at 0° C. Thereaction mixture was warmed up to RT and stirred for 16 h. TLC analysisshowed complete consumption of the starting material. The reactionmixture was quenched with sat. aq. NaHCO₃ (30 ml) and extracted withEtOAc (3×50 ml). The combined organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography (silica gel, 230-400 mesh, EtOAc—pet ether(1:3)→(3:7)) to give1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione(650 mg, 73%, colorless viscous oil). TLC system: EtOAc—pet ether (6:4);R_(f)=0.40.

Step 3:1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

To a stirred solution of N-isobutyl-N-methylamine (1.34 ml, 11.23 mmol)and MeOH/H₂O (8 ml, 1:1, v/v) was added 4N aq. HCl (1.5 ml) and thereaction mixture was stirred for 10 min at 0° C. (ice bath). A solutionof1-cyclobutylmethyl-3-(4-methoxy-benzyl)-1,3-diaza-spiro[4.5]decane-2,8-dione(1 g, 2.80 mmol) in MeOH (7 ml) and KCN (548 mg, 8.42 mmol) were addedand the reaction mixture was stirred at 45° C. for 20 h. TLC analysisshowed complete consumption of the starting material. The reactionmixture was diluted with water (30 ml), extracted with EtOAc (3×30 ml),the combined organic phase was dried over Na₂SO₄ and concentrated underreduced pressure to give1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(1.3 g, viscous yellow oil). TLC system: EtOAc—pet ether (1:1);R_(f)=0.45. The product was used for the next step without additionalpurification.

Step 4:CIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containing1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(1.3 g, 2.81 mmol) was cooled in an ice bath (˜0° C.) and a solution ofphenylmagnesium bromide (26 ml, ˜2M in THF) was added slowly at 0° C.-5°C. The ice bath was removed and the reaction mixture was stirred for 30min, then diluted with sat. aq. NH₄Cl (25 ml) and extracted with EtOAc(4×30 ml). The combined organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure to give pale yellow viscous oil.This residue was purified by column chromatography (silica gel, 230-400mesh, eluent: EtOAc—pet ether (15:85)→(2:4)) to giveCIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(135 mg, 10%, white solid). TLC system: EtOAc—pet ether (1:1); R_(f)=0.6

Step 5:CIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A round bottom flask containingCIS-1-(cyclobutylmethyl)-8-(isobutyl(methyl)amino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(130 mg, 0.25 mmol) was cooled in an ice bath and a mixture ofTFA/CH₂Cl₂ (2.6 ml, 1:1, v/v) was added slowly at 0° C.−5° C. Thereaction mixture was warmed to RT and stirred for 20 h, then quenchedwith methanolic NH₃ (10 ml, ˜10% in MeOH) and concentrated under reducedpressure to give pale yellow viscous oil. This residue was purifiedtwice by column chromatography (silica gel, 230-400 mesh, eluent:MeOH—CHCl₃ (1:99)→(2:98)) to giveCIS-1-(cyclobutyl-methyl)-8-(methyl-(2-methyl-propyl)-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-953) (65 mg, 66%, white solid). TLC system: MeOH—CHCl₃ (5:95);R_(f)=0.25; [M+H]⁺ 384.3

Synthesis of INT-958: 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

Step 1: Ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate

KOtBu (57.0 g, 508.4 mmol) was added to the solution of2-(pyridin-2-yl)acetonitrile (50.0 g, 423.7 mmol) and ethyl acrylate(89.0 g, 889.8 mmol) in THF (500 mL) at 0° C. and stirred for 16 h atRT. The reaction mixture was quenched with sat. aq. NH₄Cl and extractedwith EtOAc (2×500 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to afford 68.0g (60%; crude) of ethyl5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate as a brown liquid(TLC system: 50% ethyl acetate in petroleum ether; Rf: 0.65).

Step 2: 4-Oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile

A solution of ethyl 5-cyano-2-oxo-5-(pyridin-2-yl)cyclohexanecarboxylate(68.0 g, 250.0 mmol) was added to a mixture of conc. aq. HCl and glacialacetic acid (170 mL/510 mL) at 0° C. The reaction mixture was heated to100° C. for 16 h. All volatiles were evaporated under reduced pressure.The residue was diluted with sat. aq. NaHCO₃ and extracted with ethylacetate (3×300 mL). The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated under reduced pressure to afford 44.0g (88%) of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile INT-958 as abrown solid (TLC system: 50% ethyl acetate in pet ether; Rf: 0.45).[M+H]⁺ 201.1

Synthesis of INT-961: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Step 1: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile

A solution of 4-oxo-1-pyridin-2-yl-cyclohexane-1-carbonitrile (INT-958)(44.0 g, 220.0 mmol), ethylene glycol (27.0 g, 440.0 mmol) and PTSA (4.2g, 22.0 mmol) in toluene (450 mL) was heated to 120° C. for 16 h usingDean Stark apparatus. All volatiles were evaporated under reducedpressure. The residue was diluted with sat. aq. NaHCO₃ and extractedwith ethyl acetate (3×300 mL). The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toafford 45.0 g (85%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile as a lightbrown solid (TLC system: 50% ethyl acetate in petroleum ether; Rf:0.55).

Step 2: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide

Potassium carbonate (50.0 g, 368.84 mmol) and 30% aq. H₂O₂(210.0 mL,1844.2 mmol) were added to the solution of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (45.0 g,184.42 mmol) in DMSO (450 mL) at 0° C. and the resulting mixture wasstirred at RT for 14 h. The reaction mixture was diluted with water (1.5L) and stirred for 1 h. The precipitated solid was separated byfiltration, washed with water, petroleum ether and dried under reducedpressure to get 32.0 g (66%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide as a whitesolid. (TLC system: 10% MeOH in DCM R_(f): 0.35).

Step 3: methyl 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate

A mixture of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carboxamide(25.0 g, 95.41 mmol), sodium hypochlorite (5 wt % aq. solution, 700 mL,477.09 mmol) and KF-Al₂O₃(125.0 g) in methanol (500 mL) was heated to80° C. for 16 h. The reaction mixture was filtered through celite andthe solid residue was washed with methanol. The combined filtrate wasconcentrated under reduced pressure. The residue was diluted with waterand extracted with ethyl acetate (3×500 mL). The combined organic layerwas washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to afford 18.0 g (66%) of methyl8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate as a light brownsolid. (TLC system: 5% MeOH in DCM R_(f): 0.52.)

Step 4: 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine

A suspension of methyl8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ylcarbamate (18.0 g, 61.64mmol) in 10 wt % aq. NaOH (200 mL) was heated to 100° C. for 24 h. Thereaction mixture was filtered through celite pad, the solid residue waswashed with water and the combined filtrate was extracted with EtOAc(4×200 mL). The combined organic layer washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure to afford 12.5 g (88%) of8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine as a light brownsemi-solid. (TLC system: 5% MeOH in DCM R_(f): 0.22.).

Step 5: 4-Dimethylamino-4-pyridin-2-yl-cyclohexan-1-one

Sodium cyanoborohydride (13.7 g, 0.213 mol) was added portionwise to asolution of 8-(pyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-amine (12.5 g,53.418 mmol) and 35 wt % aq. formaldehyde (45 mL, 0.534 mol) inacetonitrile (130 mL) at 0° C. The reaction mixture was warmed up toroom temperature and stirred for 16 h. The reaction mixture was quenchedwith sat. aq. NH₄Cl and concentrated under reduced pressure. The residuewas dissolved in water and extracted with EtOAc (3×200 mL). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedunder reduced pressure to afford 10.5 g (72%) of4-dimethylamino-4-pyridin-2-yl-cyclohexan-1-one (INT-961) as a lightbrown solid. (TLC system: 5% MeOH in DCM R_(f): 0.32.). [M+H]⁺ 219.1

Synthesis of INT-965: 4-Dimethylamino-4-phenyl-cyclohexan-1-one

Step 1: 8-(Dimethylamino)-1,4-dioxaspiro 4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (52 g, 0.645 mol) was added to the solutionof 1,4-dioxaspiro-[4.5]-decan-8-one (35 g, 0.224 mmol) in MeOH (35 mL)at RT under argon atmosphere. The solution was stirred for 10 min and 40wt % aq. dimethylamine (280 mL, 2.5 mol) and KCN (32 g, 0.492 mol) weresequentially added. The reaction mixture was stirred for 48 h at RT,then diluted with water (100 mL) and extracted with EtOAc (2×200 mL).The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 44 g of8-(dimethylamino)-1,4-dioxaspiro-[4.5]-decane-8-carbonitrile (93%) as awhite solid.

Step 2: N,N-dimethyl-8-phenyl-1,4-dioxaspiro-[4.5]decan-8-amine

8-(Dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (35 g, 0.167mol) in THF (350 mL) was added to the solution of 3M phenylmagnesiumbromide in diethyl ether (556 mL, 1.67 mol) dropwise at −10° C. underargon atmosphere. The reaction mixture was stirred for 4 h at −10° C. to0° C. and then at RT for 18 h. The reaction completion was monitored byTLC. The reaction mixture was cooled to 0° C., diluted with sat. aq.NH₄Cl (1 L) and extracted with EtOAc (2×600 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 60 g of, N N-dimethyl-8-phenyl-1,4-dioxaspiro-[4.5]-decan-8-amine as a liquid.

Step 3: 4-(dimethylamino)-4-phenylcyclohexanone

A solution of N,N-dimethyl-8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine (32g, 0.123 mol) in 6N aq. HCl (320 mL) was stirred at 0° C. for 2 h andthen at RT for 18 h. The reaction completion was monitored by TLC. Thereaction mixture was extracted with DCM (2×150 mL). The aqueous layerwas basified to pH 10 with solid NaOH and extracted with ethyl acetate(2×200 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The solid residue was washedwith hexane and dried in vacuo to afford 7 g of4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (25% over 2 steps)as a brown solid. [M+H]⁺ 218.1

Synthesis of INT-966:3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

Step 1: 9,12-Dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione

KCN (93.8 g, 1441.6 mmol) and (NH₄)₂CO₃ (271.8 g, 1729.9 mmol) wereadded to the solution of 1,4-dioxaspiro[4.5]decan-8-one (150 g, 961mmol) in MeOH:H₂O (1:1 v/v) (1.92 L) at RT under argon atmosphere. Thereaction mixture was stirred at 60° C. for 16 h. The reaction completionwas monitored by TLC. The reaction mixture was cooled to 0° C., theprecipitated solid was filtered off and dried in vacuo to afford 120 g(55%) of9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione. Thefiltrate was extracted with DCM (2×1.5 L). The combined organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford additional 30 g (14%) of9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione (TLCsystem: 10% Methanol in DCM; Rf: 0.4).

Step 2:2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione

Cs₂CO₃ (258.7 g, 796.1 mmol) was added to the solution of 73a (150 g,663.4 mmol) in MeCN (1.5 L) under argon atmosphere and the reactionmixture was stirred for 30 min. A solution of p-methoxybenzyl bromide(96 mL, 663.4 mmol) was added. The reaction mixture was stirred at RTfor 48 h. The reaction completion was monitored by TLC. The reactionmixture was quenched with sat. aq. NH₄Cl (1.0 L) and the organic productwas extracted with EtOAc (2×1.5 L). The combined organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was washed with diethyl ether and pentane and dried underreduced pressure to afford 151 g (65%) of2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dioneas an off white solid (TLC system: 10% MeOH in DCM; Rf: 0.6).

Step 3:2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one

AlCl₃ (144.3 g, 1082.6 mmol) was added to a solution of LiAlH₄ (2M inTHF) (433 mL, 866.10 mmol) in THF (4.5 L) at 0° C. under argonatmosphere and the resulting mixture was stirred at RT for 1 h.2-[(4-Methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecane-1,3-dione(150 g, 433.05 mmol) was added at 0° C. The reaction mixture was stirredat RT for 16 h. The reaction completion was monitored by TLC. Thereaction mixture was cooled to 0° C., quenched with sat. aq. NaHCO₃ (500mL) and filtered through celite pad. The filtrate was extracted withEtOAc (2×2.0 L). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated in vacuo to afford 120 g (84%) of2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-oneas an off-white solid. (TLC system: 10% MeOH in DCM, Rf: 0.5).

Step 4: 3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione

A solution of2-[(4-methoxyphenyl)-methyl]-9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one(120 g, 361.03 mmol) in 6N aq. HCl (2.4 L) was stirred at 0° C. for 2 hand then at RT for 18 h. The reaction completion was monitored by TLC.The reaction mixture was extracted with DCM (2×2.0 L). The aqueous layerwas basified to pH 10 with 50% aq. NaOH and then extracted with DCM(2×2.0 L). Combined organic extracts were dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The solid residue was washedwith hexane and dried in vacuo to afford 90 g of3-[(4-Methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione(INT-966) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.4)[M+H]⁺ 289.11.

Synthesis of INT-975:CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution ofCIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reactionmixture was stirred for 30 min. 4-Methoxybenzyl bromide (4.23 mL, 29.30mmol) was added and stirring was continued at RT for 4 h. The reactioncompletion was monitored by TLC. The reaction mixture was diluted withsat. aq. NH₄Cl (150 mL) and the organic product was extracted with EtOAc(2×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated in vacuo. The reaction was carried out in 2 batches (8g×2) and the batches were combined for purification. Purification of thecrude product by flash column chromatography on silica gel (0-10%methanol in DCM) and subsequently by washing with pentane yielded 11 g(47%) ofCIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) as a white solid. [M+H]⁺ 394.2

Synthesis of INT-976:CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: 8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione

In a sealed tube 4-dimethylamino-4-phenyl-cyclohexan-1-one (INT-965) (2g, 9.22 mmol) was suspended in 40 mL EtOH/H₂O (1:1 v/v) at RT underargon atmosphere. (NH₄)₂CO₃ (3.62 g, 23.04 mmol) and KCN (0.6 g, 9.22mmol) were added. The reaction mixture was stirred at 60° C. for 18 h.The reaction mixture was cooled to 0° C. and diluted with ice-water andfiltered through a glass filter. The solid residue was dried underreduced pressure to afford8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (1.8 g,86%) as an off white crystalline solid (TLC: 80% EtOAc in hexane; Rf:0.25).

Step 2: 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro[4,5]decan-2-one

LiAlH₄ (2M in THF) (70 mL, 139.4 mmol) was added to the solution of8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decane-2,4-dione (10 g,34.8 mmol) in THF/Et₂O (2:1 v/v) (400 mL) at 0° C. under argonatmosphere. The reaction mixture was stirred for 4 h at 60° C. Thereaction completion was monitored by TLC.

The reaction mixture was cooled to 0° C., quenched with saturated Na₂SO₄solution (100 mL) and filtered through Celite pad. The filtrate wasdried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 5.7 g(59%) of 8-(dimethylamino)-8-phenyl-1, 3-diazaspiro[4,5]decan-2-one asan off white solid. (TLC system: 10% MeOH in DCM, Rf: 0.3).

Step 3: CIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A mixture of CIS- andTRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4,5]decan-2-one (8 g,29.30 mmol) was purified by preparative chiral SFC (column: ChiralcelAS-H, 60% CO₂, 40% (0.5% DEA in MeOH)) to get 5 g ofCIS-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976) asa white solid. [M+H]⁺ 274.2.

Synthesis of INT-977:CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid; 2,2,2-trifluoro-acetic acid salt

Step 1:CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester

A solution ofCIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-975) (5.0 g, 12.7 mmol) in THF (18 mL) was cooledto 0° C. and treated with LDA solution (2M in THF/heptane/ether, 25.4mL, 50.8 mmol). The resulting mixture was allowed to warm up to RT over30 min. The solution was then cooled to 0° C. again andtert-butyl-bromoacetate (5.63 mL, 38.1 mmol) was added. The reactionmixture was stirred at RT for 16 h, quenched with water and extractedwith DCM (3×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated inder reduced pressure. Purification of theresidue by column chromatography on silica gel providedCIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester (4.4 g).

Step 2:cis-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid trifluoroacetic acid salt

CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester (200 mg, 0.4 mmol) was dissolved in TFA (5 mL) andheated to reflux overnight. After cooling to RT all volatiles areremoved in vacuo. The residue was taken up in THF (1 mL) and addeddropwise to diethyl ether (20 mL). The resulting precipitate wasfiltered off and dried under reduced pressure to giveCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid; 2,2,2-trifluoro-acetic acid salt (INT-977) (119 mg) as a whitesolid. [M+H]⁺ 332.2

Synthesis of INT-978:CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide

CIS-2-(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-aceticacid (INT-977) trifluoroacetic acid salt (119 mg, 0.35 mmol) wasdissolved in DCM (5 mL). Triethylamine (0.21 mL, 1.6 mmol),dimethylamine (0.54 mL, 1.1 mmol) and T3P (0.63 mL, 1.1 mmol) weresequentially added. The reaction mixture was stirred at RT overnight,then diluted with 1 M aq. Na₂CO₃ (5 mL). The aqueous layer was extractedwith DCM (3×5 mL), the combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel to yieldCIS-2-(8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl)-N,N-dimethyl-acetamide(INT-978) (39 mg) as a white solid. [M+H]⁺ 359.2

Synthesis of INT-982:CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A solution of NaOH (2.85 g, 71.2 mmol) in DMSO (25 mL) was stirred at RTfor 10 min.CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (7.00 g, 17.8 mmol) was added and stirring was continued for15 min. 1-(Bromo-methyl)-1-methyl-cyclobutane (8.7 g, 53.4 mmol) wasadded at 0° C. The reaction mixture was heated to 60° C. for 16 h. Aftercooling down to RT, water (100 mL) was added and the mixture wasextracted with DCM (3×150 mL). The combined organic layers were washedwith water (70 mL), brine (100 mL), dried over Na₂SO₄ and concentratedunder reduced pressure. Purification of the residue by columnchromatography on silica gel providedCIS-8-(dimethylamino)-3-(4-methoxybenzyl)-1-((1-methylcyclobutyl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(6.5 g) as a light yellow solid.

Step 2:CIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To the solution ofCIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (6.66 g, 14.0 mmol) in DCM (65 mL) was added TFA (65mL) and the resulting mixture was stirred at RT for 16 h. The reactionmixture was concentrated under reduced pressure. The residue was takenup in DCM (100 mL) and water (60 mL) and basified with 2M aq. NaOH to pH10. The organic layer was separated and washed with brine (40 mL), driedover MgSO₄, filtered and concentrated under reduced pressure.Crystallization of the residue from EtOAc providedCIS-8-Dimethylamino-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-982) (3.41 g) as an off-white solid. [M+H]⁺ 356.3

Synthesis of INT-984:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) was converted intoCIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 2CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-onewas converted intoCIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-984).

Synthesis of INT-986:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (3.11 g, 13.92 mmol) was added to the solution ofCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[phenyl-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-950) (4 g, 9.28 mmol) in a mixture of acetonitrile and THF (1:1v/v, 80 mL) and the resulting mixture was stirred at RT for 16 h. Thereaction mixture was basified with 2N aq. NaOH to pH-10 and the organicproduct was extracted with DCM (3×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas stirred vigorously with a mixture of 10 wt % aq. citric acid (5 mL)and DCM (10 mL) at RT for 10 min. The reaction mixture was basified with5N aq. NaOH to pH-10 and extracted with DCM (3×10 mL). The combinedorganic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuoto give 3.5 g (crude) ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneas semi solid (TLC system: 10% MeOH in DCM; R_(f): 0.60.).

Step 2:CIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium cyanoborohydride (1.56 g, 25.17 mmol, 3 equiv.) was added to thesolution ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(3.5 g, 8.39 mmol), acetaldehyde (738 mg, 16.78 mmol, 2 equiv.) andacetic acid (0.5 mL) in methanol (20 mL). The reaction mixture wasstirred at RT for 3 h, then quenched with sat. aq. NaHCO₃ and theorganic product was extracted with DCM (3×50 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and concentrated in vacuo.Purification of the residue by flash column chromatography on silica gel(230-400 mesh) (20-25% ethyl acetate in petroleum ether) yielded 2.3 g(62%) ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one as a solid. (TLC system: 50% EtOAc in Pet. Ether;R_(f): 0.65).

Step 3:CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-986)

Sodium metal (1.18 g, 51.68 mmol, 10 equiv.) was added to liquid ammonia(−25 mL) at −78° C. The resulting mixture was stirred for 10 min at −78°C. A solution ofCIS-3-benzyl-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(2.3 g, 5.16 mmol) in THF (25 mL) was added at −78° C. The reactionmixture was stirred for 15 min, then quenched with sat. aq. NH₄Cl,warmed to RT and stirred for 1 h. The organic product was extracted withDCM (3×50 mL). The combined organic layer was washed with water, brineand concentrated under reduced pressure to afford 1.30 g (72%) ofCIS-1-(cyclobutylmethyl)-8-(ethyl(methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-986) as an off-white solid. (TLC system: 10% MeOH in DCM R_(f):0.15.). [M+H]⁺ 356.3

Synthesis of INT-987:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method as described for INT-982 step 2CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-952) was converted intoCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-987).

Synthesis of INT-988:CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium hydroxide (78.06 mg, 4.0 equiv.) was suspended in DMSO (3.5 mL),stirred for 10 minutes,8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-975) (192.0 mg, 1.0 equiv.) was added, the reaction mixture wasstirred for 5 min followed by addition of 2-(1-methoxycyclobutyl)ethyl4-methylbenzenesulfonate (416.2 mg, 3.0 equiv.) in DMSO (1.5 mL). Theresulting mixture was stirred overnight at 50° C. The reaction mixturewas quenched with water and extracted with DCM (3×20 mL). The combinedorganic phases were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue (283 mg yellow oil) waspurified by column chromatography on silica gel (eluent DCM/EtOH 98/2 to96/4) to give8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one163 mg (66%).

Step 2:CIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-988)

In analogy to the method described for INT-982 step 2CIS-8-(dimethylamino)-1-[2-(1-methoxycyclobutyl)ethyl]-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-onewas converted intoCIS-8-(dimethylamino)-1-(2-(1-methoxycyclobutyl)ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-988). Mass: m/z 386.3 (M+H)⁺.

Synthesis of INT-1008:CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one

Step 1 and step 2: ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-aminehydrochloride (INT-1004)

A mixture of 1,4-dioxa-spiro[4.5]decan-8-one (25.0 g, 160.25 mmol, 1.0eq.) and 2M solution of EtNH₂ in THF (200 ml, 2.5 eq. 400.64 mmol) inEtOH (30 ml) was stirred at RT for 48 h. The reaction mixture wasconcentrated under argon atmosphere and the residue was diluted withether (60 ml), and a freshly prepared PhLi solution was added [preparedby addition of 2.5M n-BuLi in THF (70.5 ml, 1.1 eq. 176.27 mmol) to asolution of bromobenzene (27.675 g, 1.1 eq. 176.275 mmol) in ether (100ml) at −30° C. and stirred at RT for 1 h). The reaction mixture wasstirred at RT for 1.5 h, quenched with saturated NH₄Cl solution (100 ml)at 0° C. and extracted with ethyl acetate (2×750 ml). The combinedorganic layer was washed with water (3×350 ml), brine (300 ml), driedover Na₂SO₄ and concentrated under reduced pressure. The resultingresidue was dissolved in ethyl methyl ketone (100 ml) and trimethylsilylchloride (37.5 ml) was added at 0° C. The resulting mixture was stirredat RT for 16 h. The precipitated solid was filtered off and washed withacetone followed by THF to getethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride as anoff white solid. This reaction was done in 2 batches of 25 g scale andthe yield is given for 2 combined batches. Yield: 18% (17.1 g, 57.575mmol). LCMS: m/z 262.2 (M+H)⁺.

Step 3: 4-ethylamino-4-phenyl-cyclohexanone (INT-1005)

To a solution of ethyl-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-aminehydrochloride (10.1 g, 34.0 mmol, 1 eq.) in water (37.5 ml) was addedconc. aq. HCl (62.5 ml) at 0° C. and the resulting mixture was stirredat RT for 16 h. The reaction mixture was basified with aq. NaOH (pH ˜14)at 0° C. and extracted with DCM (2×750 ml). Organic layer was washedwith water (400 ml), brine (400 ml), dried over Na₂SO₄ and concentratedunder reduced pressure to yield 4-ethylamino-4-phenyl-cyclohexanonewhich was used in the next step without further purification. Thisreaction was carried out in another batch of 15.1 g scale and the yieldis given for 2 combined batches. Yield: 92% (17.0 g, 78.34 mmol).

Step 4: cis and trans mixture of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (INT-1006 andINT-1007)

To a solution of 4-ethylamino-4-phenyl-cyclohexanone (17 g, 78.341 mmol,1.0 eq.) in EtOH (250 ml) and water (200 ml) was added (NH₄)₂CO₃ (18.8g, 195.85 mmol, 2.5 eq.) and the reaction mixture was stirred at RT for15 min. KCN (5.09 g, 78.341 mmol, 1.0 eq.) was added and stirring wascontinued at 60° C. for 18 h. The reaction mixture was cooled down toRT. The precipitated solid was filtered off, washed with water (250 ml),EtOH (300 ml), hexane (200 ml) and dried under reduced pressure to yieldcis and trans mixture of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (13.0 g,45.29 mmol, 58%) as a white solid. Yield: 58% (13 g, 45.296 mmol).LC-MS: m/z [M+1]⁺=288.2.

Step 5: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione(INT-1006)

To a solution of cis and trans mixture of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (12 g) inMeOH-DCM (1:1, 960 ml) was added a solution of L-tartaric acid in MeOH(25 ml) and the resulting mixture stirred at RT for 2 h and then kept inrefrigerator for 16 h. The precipitated solid was filtered off andwashed with MeOH-DCM (1:5, 50 ml) to get tartrate salt of8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (7.5 g) as awhite solid. To this solid sat. aq. NaHCO₃ was added (pH-8) and theresulting mixture was extracted with 25% MeOH-DCM (2×800 ml). Combinedorganic layer was washed with water (300 ml), brine (300 ml), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas triturated with 20% DCM-hexane and the resulting solid was driedunder reduced pressure to affordCIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione as whitesolid. This step was done in 2 batches (12 g & 2.4 g) and the yield isgiven for 2 combined batches. Yield: 31.2% (5.0 g, 17.421 mmol). LC-MS:m/z [M+1]⁺=288.0.

Step 6: CIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(INT-1008)

To a slurry of LiAlH₄ (793 mg, 20.91 mmol, 3.0 eq.) in THF (15 ml) wasadded a suspension ofCIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (2.0 g,6.97 mmol, 1.0 eq.) in THF (60 ml) at 0° C. and the reaction mixture washeated to 65° C. for 16 h. The reaction mixture was cooled to 0° C.,quenched with sat. aq. Na₂SO₄ (20 ml), stirred at RT for 1 h andfiltered through celite pad. The residue was washed with 15% MeOH-DCM(500 ml). The combined filtrate was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give crude product which wastriturated with 15% DCM-Hexane to affordCIS-8-ethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one (INT-1008)(1.6 g, 5.86 mmol, 84%) as a white solid. Yield: 84% (1.6 g, 5.86 mmol).LC-MS: m/z [M+1]⁺=274.2.

Synthesis of INT-1010:CIS-8-(dimethylamino)-8-phenyl-3-(prop-2-yn-1-yl)-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (INT-976)(5.0 g, 18.31 mmol, 1.0 eq.) in dry THF (500 ml) was added t-BuOK (3.07g, 27.46 mmol, 1.5 eq.) and the reaction mixture was stirred at RT for15 min. 3-Bromo-propyne (3.24 g, 13.18 mmol, 1.2 eq., 80% in toluene)was added and stirring was continued at RT for 18 h. The reactionmixture was poured into ice-water and extracted with DCM (800 ml). Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (neutralalumina; 1% MeOH/Hexane) to yieldCIS-8-(dimethylamino)-8-phenyl-3-(prop-2-yn-1-yl)-1,3-diazaspiro[4.5]decan-2-one(INT-1010) (3.0 g, 9.64 mmol, 52%) as an off white solid. Yield: 52%(3.0 g, 9.64 mmol). Mass: m/z 312.3 (M+H)⁺.

Synthesis of INT-1011: ethylCIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate

To a suspension ofCIS-8-dimethylamino-8-phenyl-3-prop-2-ynyl-1,3-diaza-spiro[4.5]decan-2-one(INT-1010) (1.0 g, 3.21 mmol, 1.0 eq.) and azidoacetic acid ethyl ester(0.37 ml, 3.21 mmol, 1.0 eq.) in t-BuOH:H₂O (1:1, 18 ml) and 1M aq.CuSO₄ (0.19 ml) was added sodium ascorbate (191 mg, 0.963 mmol, 0.3eq.). The reaction mixture was stirred at RT for 18 h, then quenchedwith water and concentrated under reduced pressure. The residue waspurified by column chromatography (silica gel neutralized with TEA; 10%MeOH/DCM) to yield ethylCIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate(INT-1011) (1.0 g, 2.27 mmol, 70%) as an off white solid. Yield: 70%(1.0 g, 2.27 mmol). Mass: m/z 441.4 (M+H)⁺.

Synthesis of INT-1012: methylCIS-2-(4-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate

To a solution ofCIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate(INT-1011) (2.0 g, 4.54 mmol, 1.0 eq.) in DMSO (30 ml) was added NaOH(727 mg, 18.18 mmol, 4.0 eq.) at RT and the reaction mixture was heatedto 70° C. for 30 min. The resulting mixture was cooled down to RT and asolution of 1-oxa-spiro[2.3]hexane (953 mg, 11.35 mmol, 2.5 eq.) in DMSO(5 ml) was added. The reaction mixture was stirred at 50° C. for 16 h,then cooled down to RT and diluted with MeOH (40 ml). Thionyl chloride(1.32 ml, 18.18 mmol, 4.0 eq.) was added at 0° C. and stirring wascontinued at RT for 16 h. The reaction mixture was concentrated underreduced pressure, then diluted with DCM (300 ml), sat. NaHCO₃ solution(200 ml) was added slowly at 0° C. and the resulting mixture was stirredat RT for 1 h. The organic layer was separated, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel; 4% MeOH/DCM) to yield methylCIS-2-(4-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate(INT-1012) (950 mg, 1.86 mmol, 41%) as brown sticky solid. Afterpurification, isolated compound was ˜60% pure and was used in the nextsteps without further purification. Yield: 41% (950 mg, 1.86 mmol).Mass: m/z 509.4 (M+H)⁺.

Synthesis of INT-1021:CIS-1-(2-methoxybenzyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-3-benzyl-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaH (0.15 g, 3.30 mmol) was added to a solution ofCIS-3-benzyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-963) (0.4 g, 1.10 mmol) in DMF (8 mL) at 0° C. over 15 min. Thereaction mixture was stirred for 5 min, 1-(bromomethyl)-2-methoxybenzene(0.33 g, 1.65 mmol) was added portionwise, ice bath was removed andstirring was continued at RT for 3 h. The resulting mixture was quenchedwith cold water (precipitation observed), the precipitate was filteredoff and dried under reduced pressure to give 450 mg (84%) ofCIS-3-benzyl-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.The crude material was used in the next step without furtherpurification. (TLC system: 10% MeOH in DCM; Rf: 0.7).

Step 2:CIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1021)

CIS-3-benzyl-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(0.45 g, 0.93 mmol) in THF (10 mL) was added to sodium metal (0.21 g,9.316 mmol) in liquid ammonia (10 mL) at −78° C. The reaction mixturewas stirred at −78° C. for 15 min, quenched with sat. aq. NH₄Cl and theorganic product was extracted with EtOAc (2×20 mL). The combined organiclayer was dried over anhydrous Na₂SO₄ and concentrated in vacuo.Purification of the residue by preparative TLC using 2% methanol in DCMas eluent gave 170 mg of solid material, which was washed with pentaneto give 150 mg (40%) ofCIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1021) as an off white solid. (TLC system: 10% MeOH in DCM; Rf:0.3). ¹H NMR (DMSO-d6): δ 7.34-7.18 (m, 7H), 6.96 (d, 1H), 6.90 (t, 1H),6.33 (s, 1H), 4.19 (s, 2H), 3.83 (s, 3H), 3.20 (s, 2H), 2.59-2.55 (m,2H), 1.98-1.90 (m, 8H), 1.37-1.30 (m, 4H). Mass: m/z 394.3 [M+H]⁺

Synthesis of INT-1022:CIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-986 (step 1)CIS-8-(dimethylamino)-1-(2-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-onewas reacted with N-iodosuccinimide to be converted intoCIS-1-(2-methoxybenzyl)-8-(methylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1022). ¹H NMR (DMSO-d6): δ 7.39 (d, 2H), 7.29 (t, 2H), 7.23-7.15(m, 3H), 6.96 (d, 1H), 6.89 (t, 1H), 6.36 (s, 1H), 4.21 (s, 2H), 3.84(s, 3H), 3.25 (s, 2H), 2.13 (m, 1H), 2.03-1.98 (m, 2H), 1.82-1.80 (m,5H), 1.64-1.58 (m, 2H), 1.34-1.31 (m, 2H). Mass: m/z 380.2 [M+H]⁺

Synthesis of INT_1023:CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one

Step 1: synthesis ofCIS-1-amino-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid

Ba(OH)₂x8H₂O (36.87 g, 117.07 mmol) was added to the solution ofCIS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (12g, 41.81 mmol) in water (450 mL) at RT. The reaction mixture was stirredat 150° C. for 8 h. The resulting mixture was cooled down to RT and(NH₄)₂CO₃ (22.97 g, 146.34 mmol) was added. The reaction mixture wasstirred at 65° C. for 8 h, then filtered through celite and theprecipitate was washed with water. The combined filtrate wasconcentrated in vacuo to afford 6.5 g of crudeCIS-1-amino-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid. Theproduct was used in the next step without further purification. (TLCsystem: 10% MeOH in DCM; Rf: 0.1).

Step 2: synthesis ofCIS-1-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-phenylcyclohexanecarboxylicacid (INT-1023)

K₂CO₃ (4.74 g, 34.34 mmol) was added to a solution ofCIS-1-amino-4-(dimethylamino)-4-phenylcyclohexanecarboxylic acid (3.0 g,11.4 mmol) in water-THF (40 mL, 1:1 v/v) at RT. After 15 min, Boc₂O(3.24 g, 14.85 mmol) was added and the reaction mixture was stirred atRT for 16 h. The resulting mixture was diluted with water, acidifiedwith glacial acetic acid (pH ˜4) and extracted with 10% MeOH in DCM(2×150 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (neutral alumina, 10% methanol in DCM as eluent)and further purified by washing with pentane to give 1.0 g (24%) ofCIS-1-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-phenylcyclohexanecarboxylicacid (INT-1023) as a white solid. (TLC system: 10% MeOH in DCM; Rf:0.10). Mass: m/z 361.2 (M−H)⁻.

Synthesis of INT-1028:CIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 2CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one(SC-2147) was treated with TFA to be converted intoCIS-8-(dimethylamino)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one(INT-1028).

Synthesis of INT-1026:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide

Titanium ethoxide (58.45 g, 256.4 mmol) was added to a solution of1,4-dioxaspiro[4.5]decan-8-one (20 g, 128.20 mmol) and2-methylpropane-2-sulfinamide (15.51 g, 128.20 mmol) in THF (200 mL) atRT and the reaction mixture was stirred at RT for 18 h. The reactionmixture was cooled to 0° C. and quenched by dropwise addition of sat.aq. NaHCO₃ (500 mL) over a period of 30 min. The organic product wasextracted with EtOAc (3×100 mL). The combined organic extracts weredried over anhydrous Na₂SO₄ and concentrated in vacuo to afford 10 g(crude) of2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide asa white solid (TLC system: 30% Ethyl acetate in hexane; Rf: 0.30).

Step 2:2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide

Phenylmagnesium bromide (1M in THF, 116 mL, 116 mmol) was added dropwiseto a solution of2-methyl-N-(1,4-dioxaspiro[4.5]decan-8-ylidene)propane-2-sulfinamide (10g, 38.61 mmol) in THF (500 mL) at −10° C. under argon atmosphere. Thereaction mixture was stirred for 2 h at −10° C. to 0° C. The reactioncompletion was monitored by TLC. The reaction mixture was quenched withsat. aq. NH₄Cl (50 mL) at 0° C. and the organic product was extractedwith EtOAc (3×100 mL). The combined organic extracts were dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel 230-400 mesh; 40-60% ethyl acetate inhexane) to yield 6.0 g (46%) of2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamideas a liquid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.30).

Step 3: 8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride

2N solution of HCl in diethyl ether (17.80 mL, 35.60 mmol) was added toa solution of2-methyl-N-(8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl)propane-2-sulfinamide(6.0 g, 17.80 mmol) in DCM (60 mL) at 0° C. The reaction mixture wasstirred at RT for 2 h. The reaction mixture was concentrated in vacuo.The residue was washed with diethyl ether to yield 3 g (crude) of8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride as a brown solid(TLC system: 5% MeOH in DCM; Rf: 0.10).

Step 4:8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine

Sodium cyanoborohydride (2.17 g, 33.45 mmol) was added to a solution of8-phenyl-1,4-dioxaspiro[4.5]decan-8-amine hydrochloride (3.0 g, 11.15mmol) and tetrahydrofuran-3-carbaldehyde (4.46 mL, 22.30 mmol) andacetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixturewas stirred at RT for 16 h. The reaction mixture was concentrated invacuo at 30° C. and to the residue sat. aq. NaHCO₃ was added. Theorganic product was extracted with DCM (3×30 mL). The combined organicextracts were dried over anhydrous Na₂SO₄ and solvent was concentratedunder reduced pressure to get 3 g (crude) of8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amineas a semi-solid (TLC system: 10% MeOH in DCM; Rf: 0.22).

Step 5:N-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine)

Sodium cyanoborohydride (1.76 g, 28.39 mmol) was added to a solution of8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine(3.0 g, 9.46 mmol), 37% formaldehyde in water (7.70 mL, 94.60 mmol) andacetic acid (0.05 mL) in methanol (30 mL) at 0° C. The reaction mixturewas stirred at RT for 16 h. The reaction mixture was concentrated invacuo and to the residue sat. aq. NaHCO₃ was added. The organic productwas extracted with DCM (3×30 mL). The combined organic extracts weredried over anhydrous Na₂SO₄ and solvent was concentrated under reducedpressure. The resulting residue was purified by column chromatography(silica gel 230-400 mesh; 5-6% MeOH in DCM) to yield 2.50 g (83%) ofN-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amineas a semi solid (TLC system: 10% MeOH in DCM; Rf: 0.25).

Step 6:4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone

5% sulfuric acid in water (25 mL) was added toN-methyl-8-phenyl-N-((tetrahydrofuran-3-yl)methyl)-1,4-dioxaspiro[4.5]decan-8-amine(2.50 g, 7.55 mmol) at 0° C. and the resulting mixture was stirred at RTfor 24 h. The reaction mixture was quenched with sat. aq. NaHCO₃ and theorganic product was extracted with DCM (2×50 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated in vacuo toafford 2.0 g (crude) of4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone as athick liquid (TLC system: 10% MeOH in DCM, Rf: 0.20).

Step 7:8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

4-(methyl((tetrahydrofuran-3-yl)methyl)amino)-4-phenylcyclohexanone(1.50 g, 5.22 mmol) was suspended in 30 mL of EtOH:H₂O (1:1 v/v) at RTunder argon atmosphere. (NH₄)₂CO₃ (1.9 g, 13.05 mmol) and KCN (0.34 g,5.22 mmol) were added. The reaction mixture was heated to 70° C. for 16h. The reaction mixture was diluted with ice-water and the organicproduct was extracted with DCM (2×50 mL). The combined organic layer wasdried over anhydrous Na₂SO₄ and concentrated in vacuo to give 1.0 g(crude) of8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dioneas a solid (TLC system: 70% Ethyl acetate in hexane; Rf: 0.18).

Step 8:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

Diastereomeric mixture of8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione(1.0 g) was separated by reverse phase preparative HPLC to afford 400 mgof isomer 1(CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione)and 60 mg of isomer 2(TRANS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione)and 300 mg of mixture of both isomers. Reverse phase preparative HPLCconditions: mobile phase: 10 mM ammonium bicarbonate inH₂O/acetonitrile, column: X-BRIDGE-C18 (150*30), 5 μm, gradient (T/B %):0/35, 8/55, 8.1/98, 10/98, 10.1/35, 13/35, flow rate: 25 ml/min,diluent: mobile phase+THF.

Step 9:CIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1026)

LiAlH₄ (1M in THF) (4.48 mL, 4.48 mmol) was added to a solution ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione(isomer-1) (0.4 g, 1.12 mmol) in THF:Et₂O (2:1 v/v, 15 mL) at 0° C.under argon atmosphere. The reaction mixture was stirred at 65° C. for16 h. The mixture was cooled to 0° C., quenched with sat. aq. Na₂SO₄(1000 mL) and filtered through celite pad. The filtrate was dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel 230-400 mesh; 5-6% MeOH in DCM) toyield 0.3 g (78%) ofCIS-8-(methyl((tetrahydrofuran-3-yl)methyl)amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1026) as an off white solid. (TLC system: 10% MeOH in DCM, Rf:0.2). LC-MS: m/z [M+1]⁺=344.2.

Synthesis of INT-1031:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-952CIS-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-974) was converted intoCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-982 step 21-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-onewas converted into1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1031).

Synthesis of INT-1037:8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Step 1: 9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one

Lithiumaluminiumhydride (2.2 equiv., 292 mmol) was suspended in THF (400mL) and the suspension was cooled to 0° C.8-(Dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one (B, 75 mg,0,261 mmol) (step 1 of INT-965) was added portionwise at 0° C. Thereaction mixture was stirred 1.5 h at 0° C., then overnight at RT andthen 2 h at 40° C. The reaction mixture was cooled down to 0° C.,quenched carefully with sat. aq. Na₂SO₄, EtOAc (400 mL) was added andthe resulting mixture was stirred for 2 h and then left without stirringfor 2 h at RT. The precipitate was filtered off and washed with EtOAcand MeOH. The resulting solid residue was suspended in methanol andstirred at RT overnight. The precipitate was filtered off and disposed.The filtrate was concentrated under reduced pressure, the residue wassuspended thoroughly in water (50 mL) at 40° C., the precipitate wasfiltered off and dried under reduced pressure to yield9,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one (11.4 g,41%). Mass: m/z 213.2 (M+H)⁺.

Step 2: 1,3-diazaspiro[4.5]decane-2,8-dione

In analogy to the method described for INT-1003 step 39,12-dioxa-2,4-diazadispiro[4.2.4̂{8}.2̂{5}]tetradecan-3-one was treatedwith conc. aq. HCl to be converted into1,3-diazaspiro[4.5]decane-2,8-dione. Mass: m/z 169.1 (M+H)⁺.

Step 3: 8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(INT-1037)

In analogy to the method described for INT-965 step 11,3-diazaspiro[4.5]decane-2,8-dione was treated with dimethyl amine andpotassium cyanide to be converted into8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(INT-1037). Mass: m/z 223.2 (M+H)⁺.

Synthesis of INT-1038:CIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one

To the suspension of8-(dimethylamino)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile (200mg, 0.90 mmol) in THF (4 mL) at RT was added dropwise 1Mbromo(m-tolyl)magnesium in THF (4 equiv., 3.6 mmol, 3.6 mL) and thereaction mixture was stirred for 1 h at RT. Additional portion of 1Mbromo(m-tolyl)magnesium in THF (1 equiv., 0.8 mL) was added. Thereaction mixture was stirred at RT overnight, then quenched withmethanol/water. Solid NH₄Cl and DCM were added to the resulting mixtureand the precipitate was filtered off. The organic phase of the filtratewas separated and the aqueous phase was extracted with DCM (3×). Thecombined organic phases were dried over anhydr. Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (DCM/MeOH, 100/0 to 65/35) to yieldCIS-8-(dimethylamino)-8-(m-tolyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1038) (81 mg, 31%). Mass: m/z 288.2 (M+H)⁺.

Synthesis of INT-1064:CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-1-acetyl-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(INT-975) (19.5 g, 49.6 mmol, 1.0 eq.) in THF (180 ml) was added 2.5Msolution of n-BuLi in hexane (39.7 ml, 99.23 mmol, 2.0 eq.) at 0° C. andthe resulting mixture was stirred for 1 h. A solution of acetyl chloride(7.7 g, 99.23 mmol, 2.0 eq.) in THF (20 ml) was added dropwise at 0° C.The cooling bath was removed, the reaction mixture was stirred at RT for16 h, then cooled down to 0° C. again, quenched with water and extractedwith ethyl acetate (2×200 ml). The combined organic extracts were washedwith brine (250 ml), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by column chromatography (silica gel;30% EtOAc/Hexane) to yieldCIS-1-acetyl-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(6.1 g, 14.02 mmol, 28%) as a light yellow sticky solid. Mass: m/z 436.3[M+H]⁺

Step 2:CIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1064)

To a solution ofCIS-1-acetyl-8-dimethylamino-3-(4-methoxy-benzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(5.0 g, 11.5 mmol, 1.0 eq.) in acetonitrile (60 ml) was added a solutioncerium(IV) ammonium nitrate (18.98 g, 34.5 mmol, 3.0 eq.) in water (60ml) at 0° C. and the reaction mixture was stirred at RT for 2 h. Thereaction mixture was quenched with aq. NaHCO₃ solution (50 ml) andextracted with ethyl acetate (2×100 ml). The combined organic layer waswashed with brine (2×100 ml), dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography(silica gel neutralized with TEA; 2/3 v/v EtOAc/Hexane) to yieldCIS-1-acetyl-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(INT-1064) as an off white solid. Yield: 61% (4.9 g, 15.55 mmol). ¹HNMR(DMSO-d6, 400 MHz), S (ppm)=7.57 (s, 1H), 7.33-7.23 (m, 5H), 3.21 (s,2H), 3.03 (t, 2H, J=12.78 Hz), 2.60 (d, 2H, J=13.32 Hz), 2.32 (s, 3H),1.89 (s, 6H), 1.37-1.32 (m, 4H). Mass: m/z 316.2 [M+H]⁺

Synthesis of INT-1059:TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (250.0g, 1.15 mol, 1.0 eq.) in EtOH (2.5 L) and water (2.1 L) was added(NH₄)₂CO₃ (276.2 g, 2.87 mol, 2.5 eq.) and the reaction mixture wasstirred at RT for 15 min. KCN (74.92 g, 1.15 mol, 1.0 eq.) was added.The reaction mixture was stirred at 60° C. for 18 h and then filtered inhot condition to get white solid which was washed with water (2.5 L),ethanol (1 L) and hexane (2.5 L). The resulting solid was dried underreduced pressure to getCIS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (223g, 0.776 mol, 65%) as a white solid. The filtrate was collected frommultiple batches (˜450 g) which contained a mixture of cis and transisomers. The filtrate was concentrated under reduced pressure and solidobtained was filtered and washed with water (1 L) and hexane (1 L).Solid material was dried under reduced pressure to get ˜100 g of amixture of cis and trans (major) isomers. Crude material was partiallydissolved in hot MeOH (600 mL) and cooled to RT, filtered throughsintered funnel, washed with MeOH (200 mL) followed by ether (150 mL)and dried to getTRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione (50g, 0.174 mmol, ˜9-10%).

Step 2: TRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1059)

In analogy to the method described for INT-976 step 2TRANS-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decane-2,4-dione wastreated with LiAlH₄ to be converted intoTRANS-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1059). Mass: m/z 274.2 (M+H)⁺.

Synthesis of INT-1065:CIS-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-1-acetyl-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-1-acetyl-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1064) (1 g, 3.17 mmol) in DMF (37 mL) was added sodium hydride (60wt % in mineral oil, 1.25 equiv., 3.96 mmol, 159 mg) portionwise at 0°C. The reaction mixture was stirred for 15 min at 0° C. and2-chloro-4-(chloromethyl)pyridine (1.25 equiv., 3.96 mmol, 0.485 mL) wasadded. The reaction mixture was stirred at RT for 2 h, then cooled downto 0° C., quenched with sat. aq. NaHCO₃ (10 mL), water (10 mL) andextracted with EtOAc (2×50 mL). Combined organic phase was washed withbrine, dried over anhydr. Na₂SO₄ and concentrated under reducedpressure. The resulting crude product was purified by flashchromatography on silica gel (eluent MeCN/DCM 98/2) to yield 1215 mg(87%) ofCIS-1-acetyl-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one.Mass: m/z 441.2 (M+H)⁺.

Step 2:CIS-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1065)

To a solution ofCIS-1-acetyl-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(1140 mg, 2.59 mmol) in THF/MeOH (2:1 v/v, 15 mL) was added 3M aq. NaOH(26 mL). The reaction mixture was stirred for 1.5 h at RT and thenextracted with EtOAc (2×50 mL). The combined organic phase was driedover anhydr. Na₂SO₄ and concentrated under reduced pressure to yield 932mg (90%) ofCIS-3-((2-chloropyridin-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1065) which was used in the next steps without additionalpurification. Mass: m/z 399.2 (M+H)⁺.

Synthesis of INT-1068 and INT-1069: CIS- andTRANS-8-(dimethylamino)-8-phenyl-1-(2,2,2-trifluoroethyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: 1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile

To a stirred solution of 4-dimethylamino-4-phenyl-cyclohexanone (50 g,230.096 mmol) in MeOH (400 mL) was added NH₄Cl (24.6 g, 460.8 mmol)followed by NH₄OH (400 mL) at RT and the reaction mixture was stirredfor 15 min. NaCN (22.5 g, 460.83 mmol) was added and the resultingmixture was stirred for 16 h at RT. The reaction mixture was extractedwith DCM (3×750 mL). Combined organic layer was washed with water (750mL), brine (750 mL), dried over Na₂SO₄ and concentrated under reducedpressure. The residue was triturated with DCM/hexane to get crude1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (50 g, 90%) asan off white solid which was used in next step without furtherpurification. LC-MS: m/z [M+H]⁺=244.2 (MW calc. 244.09).

Step 2:N-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamide

To a solution of1-amino-4-dimethylamino-4-phenyl-cyclohexanecarbonitrile (5.0 g, 20.57mmol, 1.0 eq.) in THF (100 ml) were added DIPEA (10.72 ml, 61.71 mmol,3.0 eq), trifluoroacetic acid (1.89 ml, 24.69 mmol, 1.2 eq) and T3P(18.2 ml, 30.85 mmol, 1.5 eq) at 0° C. The reaction mixture was stirredat RT for 16 h, then diluted with water (100 ml) and extracted with 10%MeOH in DCM (2×250 mL). Combined organic layer was washed with brine(100 mL), dried over Na₂SO₄ and concentrated under reduced pressure toget crudeN-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoroacetamideas a light yellow sticky material which was used in the next stepwithout further purification. LC-MS: m/z [M+1]⁺=339.9 (MW calc. 339.36).

Step 3:1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

To suspension of LiAlH₄ (4.03 g, 106.19 mmol, 6.0 eq.) in dry THF (40mL) was addedN-(1-cyano-4-dimethylamino-4-phenyl-cyclohexyl)-2,2,2-trifluoro-acetamide(6.0 g, 17.69 mmol, 1.0 eq.) in dry THF (100 mL) dropwise at 0° C. Thereaction mixture was stirred at RT for 16 h, then quenched with sat. aq.Na₂SO₄ at 0° C., excess THF was added and the resulting mixture wasstirred at RT for 2 h. The resulting suspension was filtered throughcelite and the filter cake was washed with 10% MeOH in DCM (150 mL).Combined filtrate was concentrated under reduced pressure to yield crude1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine(4.2 g, crude) as a light yellow sticky material which was directly usedin the next step without further purification. LC-MS: m/z [M+1]⁺=330.0(MW calc. 329.40).

Step 4: CIS- andTRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1068 and INT-1069)

To a solution of1-aminomethyl-N′,N′-dimethyl-4-phenyl-N-(2,2,2-trifluoro-ethyl)-cyclohexane-1,4-diamine(4.2 g, 12.76 mmol, 1.0 eq.) in toluene (60 ml) was added KOH (4.29 g,76.56 mmol, 6.0 eq.) in water (120 ml) at 0° C. followed by addition ofCOCl₂ (15.6 ml, 44.66 mmol, 3.5 eq., 20% in toluene) at 0° C. andstirred at RT for 16 h. Reaction mixture was basified with sat NaHCO₃solution and extracted with DCM (2×200 ml). Combined organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure to get crudeproduct which was purified by prep HPLC to getCIS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1068) (1.5 g) (major isomer, polar spot on TLC) andTRANS-8-dimethylamino-8-phenyl-1-(2,2,2-trifluoro-ethyl)-1,3-diaza-spiro[4.5]decan-2-one(INT-1069) as minor isomer (non-polar spot on TLC) (120 mg, 92.93% byHPLC) as off-white solids. CIS-isomer: LC-MS: m/z [M+1]⁺=356.2 (MWcalc.=355.40). HPLC: 98.53%, Column: Xbridge C-18 (100×4.6), 5μ,Diluent: MeOH, Mobile phase: A) 0.05% TFA in water; B) ACN flow rate: 1ml/min, R_(t)=5.17 min. ¹HNMR (DMSO-d₆, 400 MHz), S (ppm)=7.43-7.27 (m,5H), 6.84 (s, 1H), 3.30-3.25 (m, 4H), 2.66-2.63 (d, 2H, J=12.72 Hz),1.89 (s, 6H), 1.58-1.51 (m, 2H), 1.46-1.43 (m, 2H), 1.33-1.23 (m, 2H).

For further intermediates the synthesis in analogy to previouslydescribed methods is given in the following table. The syntheses of thebuilding blocks and intermediates have either been described previouslywithin this application or can be performed in analogy to the hereindescribed methods or by methods known to the person, skilled in the art.Such a person will also know which building blocks and intermediatesneed to be chosen for synthesis of each exemplary compound.

Inter- in analogy m/z mediate Chemical Name to method [M + H]⁺ INT-794CIS-3-(3,4-dimethoxy- benzyl)-8-(dimethylamino)- 8-phenyl-1,3-diazaspiro[4.5]decan-2-one

SC_2097 424.3 INT-796 CIS-8-Dimethylamino- 3-[(4-methoxyphenyl)-methyl]-8-(3-methoxy- propyl)-1,3-diazaspiro[4.5] decan-2-one

SC_2017 390.3 INT-797 CIS-8-(Ethyl-methyl- amino)-8-phenyl-1,3-diazaspiro[4.5]decan- 2-one

INT-976 288.2 INT-798 CIS-3-[[8-(Ethyl-methyl- amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan- 3-yl]-methyl]-benzonitrile

SC_2097 403.3 INT-949 CIS-8-Dimethylamino- 1-ethyl-8-phenyl-1,3-diazaspiro[4.5]decan-2- one

INT-984 302.2 INT-950 CIS-1-(Cyclobutyl- methyl)-8-dimethylamino-8-phenyl-3-[phenyl- methyl]-1,3-diazaspiro [4.5]decan-2-one

SC_2125 432.3 INT-954 4-Dimethylamino-4-(5- methyl-thiophen-2-yl)-cyclohexan-1-one

INT-965 238.1 INT-955 4-Dimethylamino-4- thiophen-2-yl-cyclohexan- 1-one

INT-965 224.1 INT-956 1-(1-Methyl-1H-pyrazol- 3-yl)-4-oxo-cyclohexane-1-carbonitrile

INT-958 204.1 INT-957 4-Oxo-1-pyrazin-2-yl- cyclohexane-1-carbonitrile

INT-958 202.1 INT-959 4-Dimethylamino-4-(1- methyl-1H-pyrazol-3-yl)-cyclohexan-1-one

INT-961 222.2 INT-960 4-Dimethylamino-4- pyrazin-2-yl-cyclohexan- 1-one

INT-961 220.1 INT-962 4-Dimethylamino-4-(3- methoxyphenyl)-cyclohexan-1-one

INT-965 248.2 INT-963 CIS-3-Benzyl-8- dimethylamino-8-phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-975 364.2 INT-964 4-(Ethyl-methyl-amino)- 4-phenyl-cyclohexan-1- one

INT-965 232.2 INT-967 CIS-8-Dimethylamino- 8-[4-(methoxymethyloxy)-phenyl]-3-[(4-methoxy- phenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one

SC_2017 454.3 INT-968 CIS-8-Dimethylamino- 8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxy- phenyl)-methyl]-1,3- diazaspiro[4.5]decan-2-one

SC_2017 454.3 INT-969 CIS-1-(Cyclobutyl- methyl)-8-dimethylamino-8-(4-hydroxyphenyl)-3- [(4-methoxyphenyl)- methyl]-1,3-diazaspiro[4.5]decan-2-one

SC_2018 478.3 INT-970 CIS-8-Dimethylamino-8- (4-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan-2- one

SC_2017 424.3 INT-972 CIS-8-Dimethylamino-8- (3-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]- 1,3-diazaspiro[4.5]decan-2- one

SC_2017 424.3 INT-979 CIS-8-Dimethylamino-1- (3-methoxy-propyl)-8-phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-984 346.2 INT-980 CIS-8-Dimethylamino-1- (2-methoxy-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2- one

INT-984 332.2 INT-981 CIS-8-Dimethylamino- 8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one

INT-984 316.2 INT-983 CIS-1-(Cyclopropyl- methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-984 328.2 INT-985 CIS-1-(Cyclobutyl-methyl)-8-(methyl-propyl-amino)- 8-phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-986 370.3 INT-993 4-benzyl-4-(dimethylamino) cyclohexanone

INT-965 232.3 INT-994 CIS-8-benzyl-8-(dimethyl- amino)-1,3-diazaspiro[4.5]decan-2-one

INT-976 288.2 INT-995 TRANS-8-benzyl-8- (dimethylamino)-1,3-diazaspiro[4.5]decan-2- one

INT-976 288.2 INT-997 CIS-8-(dimethylamino)- 8-(thiophen-2-yl)-1,3-diazaspiro[4.5]decan-2- one

INT-976 280.1 INT-998 TRANS-8-(dimethyl- amino)-8-(thiophen-2-yl)-1,3-diazaspiro[4.5]decan- 2-one

INT-976 280.1 INT-999 4-(dimethylamino)-4-(1- methyl-1H-benzo[d]imidazol-2-yl) cyclohexanone

INT-965 272.2 INT-1000 CIS-8-(dimethylamino)- 8-(1-methyl-1H-benzo[d]imidazol-2-yl)- 1,3-diazaspiro[4.5]decan- 2-one

INT-976 328.2 INT-1001 TRANS-8-(dimethylamino)- 8-(1-methyl-1H-benzo[d]imidazol-2-yl)-1,3-diazaspiro [4.5]decan-2-one

INT-976 328.2 INT-1009 TRANS-8-ethylamino-8- phenyl-1,3-diaza-spiro[4.5]decan-2-one

INT-1008 274.2 INT-1024 CIS-8-(dimethylamino)- 8-(3-fluorophenyl)-1,3-diazaspiro[4.5]decan-2- one

INT-977 (step 2) 292.2 INT-1025 CIS-8-(dimethylamino)-8-(4-fluorophenyl)-1,3- diazaspiro[4.5]decan-2- one

INT-974, INT-977 (step 2) 292.2 INT-1029 CIS-1-(cyclobutylmethyl)-8-(dimethylamino)-8- phenyl-3-(prop-2-yn-1-yl)-1,3-diazaspiro[4.5]decan-2- one

INT-1010 380.3 INT-1030 ethyl CIS-2-(4-((1- (cyclobutylmethyl)-8-(dimethylamino)-2-oxo- 8-phenyl-1,3-diazaspiro [4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1- yl)acetate

INT-1011 509.3 INT-1039 CIS-8-(dimethylamino)-8- (3-(trifluoromethoxy)phenyl)-1,3-diazaspiro[4.5] decan-2-one

INT-1038 358.2 INT-1040 (CIS)-8-(dimethylamino)-8-(3-(trifluoromethyl)phenyl)- 1,3-diazaspiro[4.5]decan-2- one

INT-1038 342.2 INT-1041 (CIS)-8-(dimethylamino)-8-(3-methoxyphenyl)-1,3- diazaspiro[4.5]decan-2-one

INT-1038 304.2 INT-1042 (CIS)-8-(5-chlorothiophen-2-yl)-8-(dimethylamino)- 1,3-diazaspiro[4.5]decan-2- one

INT-1038 314.1 INT-1043 (CIS)-8-(dimethylamino)-8-(3-fluoro-5-methylphenyl)- 1,3-diazaspiro[4.5]decan-2- one

INT-1038 306.2 INT-1044 (CIS)-8-(3-chlorophenyl)- 8-(dimethylamino)-1,3-diazaspiro[4.5]decan-2- one

INT-1038 308.2 INT-1047 (CIS)-8-(methyl(oxetan-3-ylmethyl)amino)-8-phenyl- 1,3-diazaspiro[4.5]decan-2- one

INT-1026 330.5 INT-1061 TRANS-1-(cyclopropyl- methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro [4.5]decan-2-one

INT-984 328.2 INT-1063 CIS-1-(cyclopropylmethyl)-8-(dimethylamino)-8-(3- fluorophenyl)-1,3-diazaspiro [4.5]decan-2-one

INT-1031 346.2 INT-1066 TRANS-1-(cyclobutyl- methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5] decan-2-one

INT-987 342.3 INT-1070 CIS-8-(dimethylamino)- 8-phenyl-1-(3,3,3-trifluoropropyl)-1,3- diazaspiro[4.5]decan-2-one

INT-1068 360.2 INT-1074 CIS-8-(dimethylamino)-8- (3-fluorophenyl)-1-((1-hydroxycyclobutyl) methyl)-1,3-diazaspiro [4.5]decan-2-one

INT-1031 376.2

Synthesis of Exemplary Compounds Synthesis of SC_2002:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaH (60% in mineral oil) (70 mg, 2.93 mmol) and1-(bromomethyl)-3-methoxy-benzene (58 mg, 0.29 mmol) were sequentiallyadded to a suspension ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneINT-987 (100 mg, 0.29 mmol) in DMF (3 mL) at 0° C. and the reactionmixture was stirred at RT for 30 min. The reaction completion wasmonitored by TLC. The reaction mixture was quenched with sat. aq. NH₄Clsolution and the organic product was extracted with EtOAc (2×12 mL). Thecombined organic layer was dried over anhydrous MgSO₄ and concentratedin vacuo. Purification of the residue by flash column chromatographyover silica gel (230-400 mesh) using 30-35% ethyl acetate in petroleumether as eluent yielded 42 mg ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2002 as solid. [M+H]⁺ 462.3

Synthesis of SC_2008:CIS-8-(Allyl-methyl-amino)-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To the solution ofCIS-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2044 (70 mg, 0.16 mmol) in MeCN (1 mL) was added potassium carbonate(216 mg, 1.56 mmol). The reaction mixture was stirred for 15 min,3-bromo-prop-1-ene (41 μL, 0.47 mmol) was added and stirring wascontinued at RT for 3 days. The mixture was then diluted with DCM,filter through celite and the filtrate was concentrated in vacuo.Purification of the residue by flash column chromatography provided 44mg ofCIS-8-(allyl-methyl-amino)-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2008 as a solid. [M+H]⁺ 488.3.

Synthesis of SC_2010:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(SC_2017) (0.2 g, 0.48 mmol) was added to the solution of NaH (60% inmineral oil) (0.08 g, 1.94 mmol) in DMF (5 mL) and the reaction mixturewas stirred at RT for 1 h. The reaction mixture was cooled to 0° C.,(bromomethyl)cyclobutane (0.21 mL, 1.94 mmol) was added dropwise andstirring was continued for 30 min at 0° C. and then for 2 days at RT.The reaction completion was monitored by TLC. The reaction mixture wasquenched with sat. aq. NH₄Cl and the organic product was extracted withEtOAc (2×10 mL). The combined organic extracts were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. Purification of theresidue by column chromatography on silica gel (100-200 mesh) using0-50% EtOAc in petroleum ether as eluent gave 0.1 g of product which wasfurther purified by preparative TLC using 30% EtOAc in petroleum etheras mobile phase to give 65 mg (28%) ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(SC_2010) as an off white solid. (TLC system: 30% EtOAc in petroleumether; R_(f): 0.6). [M+H]⁺ 480.3

Synthesis of SC_2014:CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A solution of NaOH (81 mg, 2.0 mmol) in DMSO (1 mL) was stirred at RTfor 10 min.CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2097) (200 mg, 1.52 mmol) was added and stirring was continued for15 min. Isobutyl-bromide (20 mg, 1.52 mmol) was added and the reactionmixture was heated to 60° C. for 16 h. After cooling to RT, water (100mL) was added and the resulting mixture was extracted with DCM (3×150mL). The combined organic layers were washed with water (70 mL) andbrine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.Purification of the residue by column chromatography providedCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2014 (72 mg) as a solid. [M+H]⁺ 450.3

Synthesis of SC_2017:CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1:8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile

Dimethylamine hydrochloride (76.36 g, 936.39 mmol) was added to asolution of3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decane-2,8-dione INT-966(90 g, 312.13 mmol) in MeOH (180 mL) at RT under argon atmosphere. Thesolution was stirred for 15 min and 40% aq. dimethylamine (780 mL) andKCN (48.76 g, 749.11 mmol) were sequentially added. The reaction mixturewas stirred for 48 h while being monitored by NMR. The reaction mixturewas diluted with water (1.0 L) and the organic product was extractedwith EtOAc (2×2.0 L). The combined organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford 90 g(85%) of8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrileas an off white solid (TLC system: TLC system: 10% MeOH in DCM; Rf:0.35, 0.30).

Step 2:CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

3-Fluorophenylmagnesium bromide (1M in THF) (220 mL, 219.17 mmol) wasadded dropwise to a solution of8-(dimethylamino)-3-(4-methoxybenzyl)-2-oxo-1,3-diazaspiro[4.5]decane-8-carbonitrile(15 g, 43.83 mmol) in THF (300 mL) at 0° C. under argon atmosphere. Thereaction mixture was stirred for 16 h at RT. The reaction completion wasmonitored by TLC. The reaction mixture was cooled to 0° C., quenchedwith sat. aq. NH₄Cl (200 mL) and the organic product was extracted withEtOAc (2×200 mL). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The reaction was carriedout in 4 batches (15 g×2 and 5 g×2) and the batches were purifiedtogether. Purification of the residue by flash column chromatographyover silica gel (230-400 mesh) (2 times) by using 0-20% methanol in DCMas eluent and further purified by washing with pentane yielded 5.6 g(11%) ofCIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-oneSC_2017 as off-white solid. (TLC system: 5% MeOH in DCM in presence ofammonia; Rf: 0.1). [M+H]⁺ 412.2

Synthesis of SC_2018:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

Step 1:CIS-8-(dimethylamino)-1-isobutyl-3-(4-methoxybenzyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

In analogy to the method described for INT-951 step 1CIS-8-dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(INT-968) was converted intoCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-(methoxymethoxy)phenyl)-1,3-diazaspiro[4.5]decan-2-one.

Step 2:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

TFA (0.2 mL) was added to a solution ofCIS-1-(cyclobutylmethyl)-8-(dimethylamino)-3-(4-methoxybenzyl)-8-(3-methoxyphenyl)-1,3-diazaspiro[4.5]decan-2-one(300 mg, 0.57 mmol) in DCM (1.5 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 3 h. The reaction completion was monitored by TLC.The reaction mixture was quenched with sat. aq. NaHCO₃ and the organicproduct was extracted with DCM (3×10 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. Purification of the residue by preparative TLC using 3% MeOHin DCM as a mobile phase yielded 50 mg (18%) ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(SC_2018) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.20)[M+H]⁺ 478.3

Synthesis of SC_2019:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one

KOtBu (411 mg, 3.66 mmol) was added to a solution ofCIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-987) (250 mg, 0.73 mmol) in THF (6 mL) under nitrogen atmosphereand the reaction mixture was stirred at RT for 30 min. After cooling to0° C. 3-(chloromethyl)pyridine hydrochloride (180 mg, 1.10 mmol) wasadded and the reaction mixture was stirred at 0° C. for 30 min and thenat RT for 3 days. The resulting mixture was diluted with water,extracted with DCM (3×), the combined organic layers were dried overMgSO₄, filtered and concentrated in vacuo. Purification of the residueby flash column chromatography provided 208 mg ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-di-azaspiro[4.5]decan-2-one(SC_2019). [M+H]⁺ 433.3

Synthesis of SC_2025:CIS-8-Dimethylamino-1-(2-methoxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-8-Dimethylamino-1-(2-hydroxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2024 (0.2 g, 0.42 mmol) was added to a solution of NaH (60% inmineral oil) (0.01 g, 0.42 mmol) in DMF (5 mL) at RT. The reactionmixture was stirred at RT for 30 min, then cooled to 0° C. and methyliodide (0.08 g, 1.28 mmol) was added dropwise. the resulting mixture wasstirred for 30 min at 0° C. and then for 16 h at RT. The reactioncompletion was monitored by TLC. The reaction mixture was quenched withsat. aq. NH₄Cl and the organic product was extracted with EtOAc (2×10mL). The combined organic extracts were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified bypreparative TLC using 30% EtOAc in petroleum ether as a mobile phase togive 40 mg (20%) ofCIS-8-dimethylamino-1-(2-methoxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2025) as an off white solid. (TLC system: 30% EtOAc in Pet. Ether;R_(f): 0.6). [M+H]⁺ 480.3.

Synthesis of SC_2026:CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (437 mg, 1.95 mmol) was added to a suspension ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2002) (600 mg, 1.30 mmol) in a mixture of acetonitrile and THF (1:1v/v, 20 mL) at RT and the resulting mixture was stirred at RT for 16 h.The reaction mixture was basified with 2N aq. NaOH to pH-10 and theorganic product was extracted with DCM (3×10 mL). The combined organicextracts were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was stirred vigorously with a mixture of10% aqueous citric acid solution (5 mL) and DCM (10 mL) at RT for 10min. The resulting mixture was basified with 5N aq. NaOH to pH-10 andextracted with DCM (3×10 mL). The combined organic layer was dried overanhydrous sodium sulfate and was concentrated in vacuo. The residue waspurified by preparative reverse phase HPLC [Column: KINETEX C-18(150*21.2) 5μ and mobile phase: 10 mM ammonium bicarbonate-acetonitrile]to give 120 mg (20%) ofCIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2026) as semi solid (TLC system: 10% MeOH in DCM; R_(f): 0.20.).[M+H]⁺448.3

Synthesis of SC_2028:CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-(methyl-propyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Sodium cyanoborohydride (20 mg, 0.33 mmol) was added to a solution ofCIS-1-(cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2026) (60 mg, 0.13 mmol), propionaldehyde (19 mg, 0.33 mmol) andacetic acid (0.05 mL) in methanol (5 mL) at RT. The reaction mixture wasstirred at RT for 3 h. The reaction mixture was quenched with sat. aq.NaHCO₃ and the organic product was extracted with DCM (10 mL3). Thecombined organic extracts were dried over anhydr. Na₂SO₄ andconcentrated under reduced pressure. A second batch of this reaction wascarried out starting from 100 mg ofCIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2026 in a similar manner. Both batches were combined and purified bypreparative TLC to give 45 mg (25%) ofCIS-1-(cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-(methyl-propyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2028) as semi solid (TLC system: 10% MeOH in DCM; R_(f): 0.25).[M+H]⁺490.3

Synthesis of SC_2034:CIS-8-Dimethylamino-1-(2-hydroxy-ethyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

NaH (55% in mineral oil) (0.26 g, 6.10 mmol) was added to a solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2097) (0.4 g, 1.02 mmol) in DMF (10 mL) at 0° C. The reactionmixture was stirred at 0° C. for 15 min. To the reaction mixture(2-bromoethoxy)(tert-butyl)dimethylsilane (1.45 g, 6.10 mmol) was addeddropwise over 5 min at 0° C. The reaction mixture was allowed to stir atRT for 16 h and then diluted with water (15 mL). The organic product wasextracted with ethyl acetate (3×25 mL). The combined organic extractswere dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was dissolved in THF (8 mL) and cooled to 0° C.Then a 1M TBAF solution in THF (1.8 mL, 1.81 mmol) was added at 0° C.The reaction mixture was allowed to stir at RT for 2 h. The reactionmixture was diluted with water (10 mL), the organic product wasextracted with DCM (3×25 mL). The combined organic extracts were washedwith sat. aq. NaHCO₃, water and brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. Purification by prep HPLC using 10Mm ammonium bicarbonate-acetonitrile as mobile phase yielded 93 mg ofcompound which was further washed with n-pentane (5 mL) to give 85 mg(19% after two steps) ofCIS-8-dimethyl-amino-1-(2-hydroxy-ethyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2034) as off white solid. (TLC system: 5% MeOH in DCM R_(f): 0.30).[M+H]⁺ 438.3

Synthesis of SC_2040:CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-acetonitrile

NaH (50% in mineral oil) (24 mg, 0.6 mmol) was added to a stirredsolution ofCIS-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2044) (134 mg, 0.3 mmol) in DMF (1 mL) at 0° C. Theniodoacetonitrile (0.11 mL, 1.5 mmol) was added dropwise at 0° C. over aperiod of 10 min. The reaction mixture was allowed to stir at RT for 16h. The reaction mixture was quenched with water and the organic productwas extracted with EtOAc (3×). The combined organic extracts were washedwith brine, dried over anhydrous MgSO₄, filtered and concentrated underreduced pressure. Purification of the residue by flash columnchromatography provided 13 mg ofCIS-2-[[1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-acetonitrile(SC_2040). [M+H]⁺ 487.3

Synthesis of SC_2042:CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester

CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2097 (500 mg, 1.3 mmol) was dissolved in 1.7 mL THF and LDA (2Msolution in THF, 2.5 mL) was added at 0° C. The reaction mixture wasstirred at RT for 30 min, then cooled to 0° C. andtert-butylbromoacetate (0.5 mL, 3.8 mmol) was added. The reaction wasstirred for 18 h, then diluted with water and extracted with DCM (3×10ml). The combined organic layers were dried over Na₂SO₄, concentrated invacuo and the residue was purified by flash chromatography to yieldCIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester (SC_2042) (470 mg) as a white solid. [M+H]⁺508.3

Synthesis of SC_2043:CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid 2,2,2-trifluoroacetic acid salt

CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester SC_2042 (200 mg, 0.4 mmol) was dissolved intrifluoroacetic acid (5 mL) and stirred at RT for 30 min. All volatilesare removed in vacuo to yieldCIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid 2,2,2-trifluoro-acetic acid salt SC_2043 (190 mg) as a solid.[M+H]⁺ 452.3

Synthesis of SC_2049:CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide

To a mixture ofCIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid 2,2,2-trifluoro-acetic acid salt (SC_2043)(60 mg, 0.11 mmol), n-propylamine (35 μL, 0.43 mmol) and DIPEA (109 μL,0.64 mmol) in DMF (1 ml) was added HATU (60 mg, 0.16 mmol) and thereaction mixture was stirred at RT for 16 h. The reaction mixture wasquenched with a 1M aq. NaHCO₃, diluted with water and extracted with DCM(3×). The combined organic layers were washed with water (3 mL), brine(3 ml), dried over Na₂SO₄, filtered and concentrated in vacuo. Flashcolumn chromatography of the residue providedCIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide(SC_2049) (20 mg). [M+H]⁺ 493.3

Synthesis of SC_2053:CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetonitrile

CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-pheny-1,3-diazaspiro[4.5]decan-1-yl]-acetamide(SC_2046) (37 mg, 0.083 mmol) was dissolved in EtOAc (1 mL) andtriethylamine (23 μL, 0.166 mmol) and T3P (59 μL, 0.099 mmol) weresequentially added. The reaction mixture was stirred at RT for 16 h andthen heated at reflux for another 3 h. After cooling to RT the reactionmixture was partitioned between water and DCM. The organic layer wasseparated and the aqueous layers was extracted twice with DCM. Thecombined organic layers were dried over MgSO₄, concentrated in vacuo andthe residue was purified by flash chromatography to yieldCIS-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetonitrile(SC_2053) (31 mg) as a solid. [M+H]⁺ 433.3

Synthesis of SC_2073:CIS-1-(Cyclobutyl-methyl)-8-[(2-hydroxy-ethyl)-methyl-amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-2-[[1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-aceticacid methyl ester (SC_2134) (125 mg, 0.24 mmol) in THF (1 mL) was addedlithium borohydride (2M in THF, 0.36 mL, 0.72 mmol) at RT. The reactionmixture was stirred at RT for 16 h followed by addition of anotherportion of lithium borohydride (2M in THF, 0.36 mL, 0.72 mmol). Afterstirring at RT for 16 h, the reaction mixture was quenched with water.The organic layer was separated, washed with a 1M aq. NaOH and water,dried over MgSO₄, filtered and concentrated in vacuo. Purification ofthe residue by flash chromatography provided 37 mg ofCIS-1-(cyclobutyl-methyl)-8-[(2-hydroxy-ethyl)-methyl-amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2073). [M+H]⁺ 492.3

Synthesis of SC_2087:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[4-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

Powdered sodium hydroxide (21 mg, 0.5 mmol) was dissolved in 0.2 mL ofdry DMSO. After stirring at RT for 30 minCIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2089) (60 mg, 0.13 mmol) was added and the resulting mixture wasstirred for another 30 min. Then2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl 4-methylbenzenesulfonate(prepared via tosylation of 2,5,8,11,14,17,20,23-octaoxapentacosan-25-olfollowing standard procedures) (216 mg, 0.4 mmol) was added. Thereaction mixture was stirred at 60° C. for 16 h. The reaction mixturewas quenched with water and the organic product was extracted with DCM(2×20 mL). The combined organic extracts were dried over anhydrousNa₂SO₄, concentrated in vacuo and the residue was purified by flashchromatography to yieldCIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[[4-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2087) (25 mg) as a white solid. [M+H]⁺ 814.5

Synthesis of SC_2089:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2125) (153 mg, 0.33 mmol) was dissolved in DCM (7 mL) and borontribromide (1M solution in DCM, 1.3 mL) was added at 0° C. The reactionwas stirred for 18 h, then water and methanol (1:1 mixture, 6 mL) wasadded. The reaction mixture was extracted with DCM (3×10 ml). Thecombined organic layers were dried over Na₂SO₄, concentrated in vacuoand the residue was purified by flash chromatography to yieldCIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2089) (21 mg) as a white solid. [M+H]⁺ 448.3

Synthesis of SC_2093:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfanyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2136) (109 mg) was dissolved in methanol (3 mL) and water (2 mL) andoxone (105 mg) was added at RT. The reaction mixture was stirred for 24h, another portion of oxone (105 mg) was added, the reaction mixture wasstirred for 12 h at RT, then diluted with water and extracted with DCM(3×10 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyto yieldCIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2093) as a white solid. [M+H]⁺ 510.3

Synthesis of SC_2097:CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

KOtBu (1M in THF) (29.30 mL, 29.30 mmol) was added to the solution ofCIS-8-Dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one INT-976 (8.0g, 29.30 mmol) in THF (160 mL) under argon atmosphere and the reactionmixture was stirred for 30 min. 4-Methoxybenzyl bromide (4.23 mL, 29.30mmol) was added and stirring was continued at RT for 4 h. The reactioncompletion was monitored by TLC. The reaction mixture was diluted withsat. aq. NH₄Cl (150 mL) and the organic product was extracted with EtOAc(2×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated in vacuo. The reaction was carried out in 2 batches (8g×2) and the batches were combined for purification. Purification of thecrude product by flash column chromatography on silica gel (0-10%methanol in DCM) and subsequently by washing with pentane yielded 11 g(47%) ofCIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2097) as a white solid. [M+H]⁺ 394.2

Synthesis of SC_2107:CIS-8-Dimethylamino-1-(3-hydroxy-3-methyl-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

50 wt % aq. sulphuric acid (0.57 mL) was added to the solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methyl-but-2-enyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2135) (0.25 g, 0.54 mmol) in 1,4-dioxane (5.75 mL) at RT and thereaction mixture was stirred for 3 h at RT. The reaction mixture wasquenched with sat. aq. NaHCO₃ and the organic product was extracted withethyl acetate (2×10 mL).

The combined organic extracts were dried over anhydr. Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by reversephase preparative HPLC to give 0.04 g (15%) ofCIS-8-dimethylamino-1-(3-hydroxy-3-methyl-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-on(SC_2107) as an off white solid. (TLC system: 10% MeOH in DCM; Rf: 0.4).[M+H]⁺ 480.3

Synthesis of SC_2109:CIS-2-[[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide

30% aq. H₂O₂ (0.3 mL, 2.54 mmol) was added to a solution ofCIS-2-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile(SC_2138) (0.4 g, 0.85 mmol) in DMSO (8 mL) at 0° C. A solution ofpotassium hydroxide (0.23 g, 4.23 mmol) in water (0.5 mL) was addeddropwise. The reaction mixture was allowed to warm up to RT and stirredfor 30 min and then quenched with cold water (20 mL). The precipitatedproduct was filtered off and washed with water. Purification bypreparative TLC using 5% methanol in DCM as mobile phase yielded 78 mgof target compound which was further washed with n-pentane (5 mL) togive 70 mg (17%) ofCIS-2-[[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide(SC_2109) as an off-white solid. (TLC system: 10% MeOH in DCM R_(f):0.4). [M+H]⁺ 491.3

Synthesis of SC_2123:CIS-8-amino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

N-Iodosuccinimide (233 mg, 1.035 mmol) was added to a solution ofCIS-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2026) (320 mg, 0.690 mmol) in a mixture of acetonitrile and THF (1:1v/v, 30 mL) at 0° C. and the resulting mixture was stirred for 5 h atRT. The reaction mixture was cooled to 0° C. and another portion ofN-Iodosuccinimide (233 mg, 1.035 mmol) was added. The reaction mixturewas allowed to warm up to RT and was stirred for further 11 h. Thereaction mixture was basified with 2N aq. NaOH to pH-10 and the organicproduct was extracted with ethyl acetate (3×30 mL). The combined organicextracts were dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by preparative TLC by using3% methanol in DCM as a mobile phase to give 100 mg of target compoundwhich was further purified by preparative reverse phase HPLC to give 65mg (21%) ofCIS-8-amino-1-((1-hydroxycyclobutyl)methyl)-3-(4-methoxybenzyl)-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(SC_2123) as an off-white solid (TLC system: 5% MeOH in DCM; R_(f):0.40.). [M+H]⁺ 450.3

Synthesis of SC_2124:CIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one

NaOH (0.53 g, 13.26 mmol) was added to a solution ofCIS-8-dimethylamino-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-oneINT-795 (1 g, 2.65 mmol) in DMSO (50 mL) under argon atmosphere at RTand the reaction mixture was stirred at 70° C. for 30 min.(1-(Tert-butyldimethylsilyloxy)cyclobutyl)methyl-4-methylbenzenesulfonate(2.94 g, 7.95 mmol) was added and stirring was continued for 2 days at70° C. The reaction completion was monitored by TLC. The reactionmixture was diluted with sat. aq. NaHCO₃ (20 mL) and the organic productwas extracted with EtOAc (4×50 mL). The combined organic layer was driedover anhydr. Na₂SO₄ and concentrated in vacuo. The crude product waspurified by column chromatography (using 230-400 mesh silica gel and2-5% MeOH in DCM as eluent) to afford 250 mg of product which wasfurther purified by prep. TLC (4% MeOH: DCM as an eluent) followed bywashing with pentane to yield 133 mg (11%) ofCIS-8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one(SC_2124) as an off-white solid. (TLC system: 10% MeOH in DCM; Rf: 0.8).[M+H]⁺ 462.3

Synthesis of SC_2125:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one (SC_2097) (10 g, 25 mmol) in 500 mL THF was added KOtBu(7.1 g, 63 mmol) at 50° C. The reaction mixture was heated up to refluxand cyclobutylmethylbromide (11.3 g, 76 mmol) was added quickly in oneportion. After 12 h new portions of KOtBu (7.1 g) andcyclobutylmethylbromide (11.3 g) were added and the reaction mixture wasallowed to stir for 2 h at reflux and was then cooled to RT. Water (150mL) was added and the organic layer separated. The aqueous layer wasextracted with ethyl acetate (3×300 mL). The combined organic layerswere dried over Na₂SO₄ and then concentrated in vacuo. The residue wasfiltered through a pad of silica gel using DCM/MeOH (19/1 v/v). Thefiltrate was concentrated in vacuo and the resulting solid wasrecrystallized from hot ethanol to yield 7.8 g ofCIS-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one(SC_2125). [M+H]⁺ 461.3

Synthesis of SC_2136:CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfanyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

CIS-3-[(3-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diaza-spiro[4.5]decan-2-one(SC_2137) (100 mg, 0.2 mmol), sodium thiomethoxide (20 mg, 0.3 mmol),Pd₂(dba)₃ (8 mg, 0.02 mmol) and9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene (10 mg, 0.02 mmol) wereplaced in an oven dried flask. After three vacuum/nitrogen purge cycles,toluene (2 mL) and DIPEA (66 μL, 0.4 mmol) were added and the resultingsuspension was heated to 100° C. for 24 h. The reaction mixture wascooled to RT, water was added and the mixture was extracted with DCM(3×5 mL). The combined organic layers were dried over Na₂SO₄,concentrated in vacuo and the residue was purified by flashchromatography to yieldCIS-1-(cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfanyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2136) as a white solid. [M+H]⁺ 478.3

Synthesis of SC_2143:CIS-3-((1H-1,2,3-triazol-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a solution ofCIS-8-dimethylamino-8-phenyl-3-prop-2-ynyl-1,3-diaza-spiro[4.5]decan-2-one(INT-1010) (1.0 g, 3.21 mmol, 1.0 eq.) in dioxane/MeOH (50 ml, 9:1) wereadded sodium azide (418 mg, 6.42 mmol, 2.0 eq.) and cuprous chloride (32mg, 0.32 mmol, 0.1 eq.) at RT. The reaction mixture was stirred at 80°C. for 18 h, then quenched with water and concentrated under reducedpressure. The resulting residue was purified by column chromatography(silica gel neutralized with aq. NH₃; 0.5% aq NH₃ in 10% MeOH/DCM) toyieldCIS-3-((1H-1,2,3-triazol-4-yl)methyl)-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2143) (600 mg, 1.69 mmol, 52%) as an off white solid. Yield: 52%(600 mg, 1.69 mmol). ¹HNMR (DMSO-d₆, 400 MHz), S (ppm)=14.84 (bs, 1H),7.65 (s, 1H), 7.32-7.24 (m, 5H), 6.93 (bs, 1H), 4.27 (s, 2H), 2.98 (s,2H), 2.28 (bs, 2H), 1.92 (s, 6H), 1.76 (bs, 4H), 1.31 (bs, 2H). Mass:m/z 355.0 (M+H)⁺.

Synthesis of SC_2144:CIS-8-(dimethylamino)-3-((1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

To a suspension of LiAlH₄ (207 mg, 5.45 mmol, 3.0 eq.) in dry THF (20ml) was added ethylCIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate(INT-1011) (800 mg, 1.82 mmol, 1.0 eq.) in dry THF (20 ml) dropwise at0° C. and the resulting mixture was stirred at RT for 1 h. The reactionmixture was quenched with sat. aq. Na₂SO₄, excess THF was added and theresulting mixture was stirred at RT for 1 h. The reaction mixture wasfiltered through celite and washed with THF. The filtrate wasconcentrated under reduced pressure to get crude product which waspurified by column chromatography (silica gel, neutralized with aq. NH₃;1% aq NH₃ in 20% MeOH/DCM) to yieldCIS-8-(dimethylamino)-3-((1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2144) (450 mg, 1.13 mmol, 62%) as a white solid. Yield: 62% (450 mg,1.13 mmol). ¹HNMR (DMSO-d₆, 400 MHz), S (ppm)=7.86 (s, 1H), 7.36-7.22(m, 5H), 6.89 (bs, 1H), 4.97 (t, 1H, J=5.3 Hz), 4.34 (t, 2H, J=5.42 Hz),4.24 (s, 2H), 3.72 (q, 2H, J=5.32 Hz), 3.01 (s, 2H), 2.30 (bs, 2H), 1.91(s, 6H), 1.77-1.75 (m, 4H), 1.33-1.31 (m, 2H). Mass: m/z 399.1 (M+H)⁺.

Synthesis of SC_2145:CIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetamide

To a solution ofCIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetate(INT-1011) (300 mg, 0.68 mmol, 1.0 eq.) in MeOH (6 ml) was added 7 M NH₃solution in MeOH (2 ml) at RT and the reaction mixture was stirred at80° C. in a sealed tube for 18 h. The reaction mixture was cooled downto RT and concentrated under reduced pressure. The crude product waspurified by column chromatography (silica gel, neutralized with TEA; 2%aq. NH₃ in 20% MeOH/DCM) to yieldCIS-2-(4-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-1H-1,2,3-triazol-1-yl)acetamide(SC_2145) (220 mg, 0.54 mmol, 78%) as an off white solid. Yield: 78%(220 mg, 0.54 mmol). ¹HNMR (DMSO-d₆, 400 MHz), S (ppm)=7.85 (s, 1H),7.67 (s, 1H), 7.34-7.22 (m, 6H), 6.93 (bs, 1H), 5.00 (s, 2H), 4.25 (s,2H), 3.01 (s, 2H), 2.30 (bs, 2H), 1.92 (s, 6H), 1.76 (bs, 4H), 1.31 (bs,2H). Mass: m/z 412.3 (M+H)⁺.

Synthesis of SC_2147:CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one

CIS-8-(dimethylamino)-3-[(4-methoxyphenyl)methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2097) (500 mg, 1.271 mmol) was dissolved in THF (8 mL) undernitrogen atmosphere and the solution was cooled down to −78° C.[Bis(trimethylsilyl)amino]lithium (1M in THF, 1.5 equiv., 1.906 mmol,1.9 mL) was added dropwise and the reaction mixture was stirred at −78°C. for 30 min, then at 0° C. for 30 min. The reaction mixture was cooleddown to −78° C. again and the solution of p-toluenesulfonyl chloride(1.5 equiv., 1.906 mmol) in THF (5 mL) was added. The reaction mixturewas stirred further 2.5 h at −78° C. and then the temperature wasallowed to increase to RT overnight. The reaction mixture was quenchedby the addition of sat. aq. NaHCO₃ (20 mL). The aqueous phase wasextracted with EtOAc (3×40 mL). The combined organic extracts werewashed with brine (30 mL), dried over MgSO₄ and concentrated underreduced pressure. Purification by flash chromatography on silica gel(elution with gradient DCM/EtOH 100/0 to 97/3) yielded 281 mg (40%) ofCIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one(SC_2147). ¹H NMR (600 MHz, DMSO) δ 7.90-7.84 (m, 2H), 7.47-7.40 (m,2H), 7.42-7.27 (m, 4H), 7.27-7.22 (m, 1H), 7.15-7.06 (m, 2H), 6.92-6.83(m, 2H), 4.16 (s, 2H), 3.72 (s, 3H), 3.24 (s, 2H), 2.99 (ddd, 2H),2.70-2.62 (m, 2H), 2.42 (s, 3H), 2.01 (s, 6H), 1.56-1.49 (m, 2H), 1.31(td, 2H). Mass: m/z 548.3 (M+H)⁺.

Synthesis of SC_2170:CIS-8-(dimethylamino)-8-phenyl-3-(2-phenylpropan-2-yl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: synthesis of tert-butylCIS-4-(dimethylamino)-4-phenyl-1-(2-phenylpropan-2-ylcarbamoyl)cyclohexylcarbamate

To a stirred solution ofCIS-1-(tert-butoxycarbonylamino)-4-(dimethylamino)-4-phenylcyclohexanecarboxylicacid (INT-1023) (1 g, 2.76 mmol) in DMF (15 mL) were addeddiisopropylethyl amine (1.78 g, 13.81 mmol) and HATU (2.09 g, 5.52 mmol)at 0° C. The reaction mixture was stirred at 0° C. for 45 min and then2-phenylpropan-2-amine (0.74 g, 5.52 mmol) was added. The reactionmixture was warmed to RT and stirred for 16 h. The reaction mixture wasquenched with sat. aq. NaHCO₃ and the organic product was extracted withEtOAc (3×25 mL). The combined organic extracts were dried over anhydr.Na₂SO₄ and concentrated under reduced pressure. Purification of theresidue by flash column chromatography (silica gel 230-400 mesh) using5-8% methanol in DCM as eluent gave 0.7 g (52%) of tert-butylCIS-4-(dimethylamino)-4-phenyl-1-(2-phenylpropan-2-ylcarbamoyl)cyclohexylcarbamateas a liquid. (TLC system: 10% MeOH in DCM a Rf: 0.30).

Step 2: synthesis ofCIS-1-amino-4-(dimethylamino)-4-phenyl-N-(2-phenylpropan-2-yl)cyclohexanecarboxamidehydrochloride

4N HCl in dioxane (15 mL) was added to a stirred solution of tert-butylCIS-4-(dimethylamino)-4-phenyl-1-(2-phenylpropan-2-ylcarbamoyl)cyclohexylcarbamate(0.7 g, 1.46 mmol) in DCM (15 mL) at 0° C. The reaction mixture wasstirred at RT for 2 h and then concentrated under reduced pressure toafford 0.7 g ofCIS-1-amino-4-(dimethylamino)-4-phenyl-N-(2-phenylpropan-2-yl)cyclohexanecarboxamidehydrochloride as an off-white solid. The product was used in the nextstep without additional purification. (TLC system: 10% MeOH in DCM a Rf:0.20).

Step 3: synthesis ofCIS-N,N-dimethyl-1-phenyl-4-((2-phenylpropan-2-ylamino)methyl)cyclohexane-1,4-diamine

A solution ofCIS-1-amino-4-(dimethylamino)-4-phenyl-N-(2-phenylpropan-2-yl)cyclohexanecarboxamide(0.7 g, 1.84 mmol) in THF (10 mL) was added to BH₃×THF solution (1M inTHF, 18 mL, 18.46 mmol) at RT. The resulting mixture was refluxed for 2h. The reaction mixture was cooled to 0° C. and slowly quenched with 6NHCl (20 mL). The aqueous layer was extracted with EtOAc and thenbasified (pH-10) with 20% aq. NaOH. The organic product was extractedwith 10% MeOH/DCM (20 mL×4). The combined organic layer was washed withbrine, dried over anhydr. Na₂SO₄ and concentrated in vacuo to give 0.3 gofCIS-N,N-dimethyl-1-phenyl-4-((2-phenylpropan-2-ylamino)methyl)cyclohexane-1,4-diamineas a liquid. The product was used in the next step without additionalpurification. (TLC system: 10 vol % methanol in DCM, Rf: 0.10).

Step 3: synthesis ofCIS-8-(dimethylamino)-8-phenyl-3-(2-phenylpropan-2-yl)-1,3-diazaspiro[4.5]decan-2-oneSC_2170

1,1′-Carbonyldiimidazole (0.90 g, 5.58 mmol) was added to a solution ofCIS-N,N-dimethyl-1-phenyl-4-((2-phenylpropan-2-ylamino)methyl)cyclohexane-1,4-diamine(1.7 g, 4.65 mmol) in DMF (20 mL) at RT. The reaction mixture wasstirred at RT for 16 h. The reaction mixture was quenched with coldwater, the precipitated solid was filtered off and dried under reducedpressure to give the product which was further purified by preparativeHPLC (column: Column: Kinetex-C18 (150*21.2 mm) 5 μm, mobile phase: 0.1%formic acid in water (A): Acetonitrile(B), gradient: T/% B: 0/20, 7/50,7.1/98, 9/98, 9.1/20, 12/20, flow rate: 18 ml/min, diluent: mobilephase+THF) to yield 0.83 g (55%) ofCIS-8-(dimethylamino)-8-phenyl-3-(2-phenylpropan-2-yl)-1,3-diazaspiro[4.5]decan-2-one(SC_2170) as a white solid. (TLC system: 10% MeOH in DCM Rf: 0.30). 1HNMR (DMSO-d6): δ 7.36-7.22 (m, 9H), 7.16-7.13 (m, 1H), 6.64 (s, 1H),3.10 (s, 2H), 2.28 (m, 2H), 1.93-1.79 (m, 10H), 1.52 (s, 6H), 1.37 (m,2H). Mass: m/z 392.2 [M+H]⁺.

Synthesis of SC_2180:CIS-8-(dimethylamino)-8-phenyl-3-(pyridin-4-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one

Step 1: synthesis ofCIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one

CIS-8-(dimethylamino)-8-phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one(INT-1028) (200 mg, 0.47 mmol, 1 equiv.) was dissolved in DMF (3.6 mL)under argon atmosphere and the solution was cooled down to 0° C. Sodiumhydride (60 wt % in mineral oil, 2.1 equiv., 0.98 mmol, 39 mg) was addedand the reaction mixture was stirred at RT for 15 min.4-(Bromomethyl)pyridine hydrobromide (1.05 equiv., 0.49 mmol, 124 mg)was added at 0° C. The reaction mixture was stirred overnight at RT,then quenched with sat. aq. NaHCO₃ (2 mL) and water (2 mL) and extractedwith EtOAc (2×15 mL). The combined organic extract was washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel (100%acetonitrile) to yieldCIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one(112 mg, 46%). Mass: m/z 519.2 [M+H]⁺.

Step 2: synthesis ofCIS-8-(dimethylamino)-8-phenyl-3-(pyridin-4-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one(SC_2180)

CIS-8-(dimethylamino)-3-(4-methoxybenzyl)-8-phenyl-1-tosyl-1,3-diazaspiro[4.5]decan-2-one(110 mg, 0.212 mmol, 1 equiv.) was dissolved in THF (2 mL) and MeOH (4.4mL) under argon atmosphere. Magnesium turnings (103 mg, 4.24 mmol, 20equiv.) were added and the resulting mixture was stirred at RT for 18 h.The reaction mixture was diluted with DCM (30 mL) and water (10 mL),stirred at RT for 1.5 h, filtered through celite and the solid residuewas washed with DCM (3×). The organic phase of the filtrate wasseparated and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel (EtOH 100% to EtOH/MeOH70/30) to yield 33 mg (43%) ofCIS-8-(dimethylamino)-8-phenyl-3-(pyridin-4-ylmethyl)-1,3-diazaspiro[4.5]decan-2-one(SC_2180). ¹H NMR (600 MHz, DMSO-d6) δ 8.52-8.47 (m, 2H), 7.36-7.28 (m,4H), 7.25-7.21 (m, 1H), 7.21-7.17 (m, 2H), 7.01 (s, 1H), 4.23 (s, 2H),2.98 (s, 2H), 2.37-2.22 (m, 2H), 1.93 (s, 6H), 1.87-1.61 (m, 4H),1.42-1.29 (m, 2H). Mass: m/z 365.2 [M+H]⁺.

Synthesis of SC_2183:CIS-8-(dimethylamino)-3-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one

A mixture of3-[(2-chloro-4-pyridyl)methyl]-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1065) (100 mg, 0.251 mmol), 1-methylpiperazine (50 equiv., 12.54mmol, 1.39 mL) and DIPEA (5 equiv., 1.25 mmol, 0.22 mL) was stirred at140° C. under microwave irradiation until complete conversion ofINT-1065 (LCMS control). The reaction mixture was diluted with 2 N aq.NaOH and EtOAc, the organic phase was separated, washed with brine,dried over anhydr. Na₂SO₄ and concentrated under reduced pressure. Theresulting crude product was purified by flash chromatography on silicagel (eluent gradient 0.2 N NH₃ in MeOH/EtOH/DCM 10/40/50 to 25/25/50v/v/v) to yieldCIS-8-(dimethylamino)-3-((2-(4-methylpiperazin-1-yl)pyridin-4-yl)methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(SC_2183) (87 mg, 75%). ¹H NMR (600 MHz, DMSO) δ 8.02 (d, 1H), 7.36-7.30(m, 2H), 7.31-7.26 (m, 2H), 7.23 (td, 1H), 6.94 (s, 1H), 6.58 (s, 1H),6.45 (dd, 1H), 4.12 (s, 2H), 3.45-3.39 (m, 4H), 2.94 (s, 2H), 2.36 (t,4H), 2.33-2.22 (m, 2H), 2.19 (s, 3H), 1.92 (s, 6H), 1.86-1.62 (m, 4H),1.34 (t, 2H). Mass: m/z 463.3 (M+H)⁺.

Synthesis of SC_2186:CIS-8-(dimethylamino)-8-phenyl-3-((2-(piperazin-1-yl)pyridin-4-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one

A mixture of3-[(2-chloro-4-pyridyl)methyl]-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one(INT-1065) (100 mg, 0.251 mmol), piperazine (1.5 equiv., 0.38 mmol, 32mg), DIPEA (5 equiv., 1.25 mmol, 0.22 mL) and n-butanol (1 mL) wasstirred 4 h at 140° C. under microwave irradiation. A new portion ofpiperazine (4.5 equiv, 1.13 mmol, 97 mg) was added and the reactionmixture was stirred further 16 h at 140° C. under microwave irradiation.The resulting mixture was concentrated under reduced pressure, taken inwater/EtOAc, organic phase separated, aqueous phase extracted withEtOAc. The combined organic phase was washed with brine, dried overanhydr. Na₂SO₄ and concentrated under reduced pressure. The resultingcrude product was purified by flash chromatography on silica gel (eluentgradient 0.2 N NH₃ in MeOH/EtOH/DCM 0/20/80 to 30/0/70 v/v/v) to yieldCIS-8-(dimethylamino)-8-phenyl-3-((2-(piperazin-1-yl)pyridin-4-yl)methyl)-1,3-diazaspiro[4.5]decan-2-one(SC_2186) (48 mg, 43%). ¹H NMR (600 MHz, CDCl3) δ 8.13-8.09 (m, 1H),7.37 (t, 2H), 7.31-7.24 (m, 3H), 6.49 (d, 2H), 5.20-5.16 (m, 1H), 4.25(s, 2H), 3.51-3.46 (m, 4H), 3.01-2.95 (m, 6H), 2.18-2.09 (m, 2H), 2.05(s, 6H), 2.03-1.92 (m, 2H), 1.92-1.84 (m, 2H), 1.50-1.42 (m, 2H). Mass:m/z 449.3 (M+H)⁺.

For further exemplary compounds the last synthesis step in analogy topreviously described methods is given in the following table. Thesyntheses of the building blocks and intermediates have either beendescribed previously within this application or can be performed inanalogy to the herein described methods or by methods known to theperson, skilled in the art. Such a person will also know which buildingblocks and intermediates need to be chosen for synthesis of eachexemplary compound.

Example Chemical Name Reactant I SC_2001CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methylsulfonyl- SC_2136phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2003CIS-8-Dimethylamino-1-isopropyl-3-[(4-methoxyphenyl)-methyl]-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2004CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4- SC_2097methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2005CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8- SC_2026[methyl-(2-methyl-propyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2006CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl- SC_20921,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2007CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyrazin-2- INT-987yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2009CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl- SC_20851,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2011CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-3- SC_2016[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2012CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-methoxyphenyl)- SC_21393-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2013CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-methoxyphenyl)- SC_21403-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2015CIS-1-Butyl-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2016CIS-8-Dimethylamino-8-(4-fluorophenyl)-3-[(4-methoxyphenyl)- INT-966methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2020CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[3-[2-[2-[2-[2-[2-(2-SC_2089 methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2021CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-hydroxyphenyl)- INT-9673-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-onehydrochloride SC_2022CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(3- INT-799methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2023CIS-1-(Cyclopentyl-methyl)-8-dimethylamino-3-[(4- SC_2097methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2024CIS-8-Dimethylamino-1-(2-hydroxy-2-methyl-propyl)-3-[(4- SC_2097methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2027CIS-3-[[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8- INT-798phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2029CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(3- SC_2026methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2030CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionitrile SC_2031CIS-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-(pyridin-3-yl-SC_2019 methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2032CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(oxetan-3- SC_2097yl-methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2033CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3- INT-986(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2035CIS-8-Dimethylamino-1-(2,2-dimethyl-propyl)-3-[(4- SC_2097methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2036CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methyl- SC_2097butyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2037CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-[3- SC_2097(trifluoromethyloxy)-propyl]-1,3-diazaspiro[4.5]decan-2-one SC_2038CIS-1-(2-Cyclobutyl-ethyl)-8-dimethylamino-3-[(4-methoxyphenyl)- SC_2097methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2039CIS-1-[(3,3-Difluoro-cyclobutyl)-methyl]-8-dimethylamino-3-[(4- SC_2097methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2041CIS-1-(Cyclobutyl-methyl)-8-[(2-methoxy-ethyl)-methyl-amino]-3- SC_2044[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2- oneSC_2044 CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-SC_2125 methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2045CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetic acid methyl ester SC_2046CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2043phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide SC_2047CIS-1-Benzyl-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2048CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2043phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-acetamide SC_2050CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methoxy- SC_2097propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2051CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4- SC_799methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2052CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-3-[(4-methoxyphenyl)- SC_2097methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2054CIS-8-Dimethylamino-1-hexyl-3-[(4-methoxyphenyl)-methyl]-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2055CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1- SC_2097(tetrahydro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2056CIS-1-(Cyclohexyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)- SC_2097methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2057CIS-N-(Cyano-methyl)-2-[8-dimethylamino-3-[(4-methoxyphenyl)- SC_2043methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide SC_2058CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1- SC_2097(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2059CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3-methoxy- INT-966propyl)-1,3-diazaspiro[4.5]decan-2-one SC_2060CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2043phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-(2-methoxy-ethyl)- acetamideSC_2062 CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-oxo-2-SC_2043 pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-oneSC_2063 CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-SC_2043 phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamideSC_2064 CIS-N-(1-Cyano-cyclopropyl)-2-[8-dimethylamino-3-[(4- SC_2043methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide SC_2065CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2043phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-N-propyl-acetamideSC_2066 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-SC_2059 methyl]-8-(3-methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-oneSC_2067 CIS-8-Dimethylamino-1-(3-hydroxy-propyl)-3-[(4-methoxyphenyl)-SC_2097 methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2068CIS-8-Dimethylamino-1-(4-methoxy-butyl)-3-[(4-methoxyphenyl)- SC_2097methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2069CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[(1-methyl- SC_2097cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2070CIS-8-Dimethylamino-1-[(1-hydroxy-cyclohexyl)-methyl]-3-[(4- SC_2097methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2071CIS-5-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-1-yl]-pentanenitrile SC_2072CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2132phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionamide SC_2074CIS-1-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-cyclobutane-1-carbonitrile SC_2075CIS-8-Dimethylamino-1-[(1-hydroxy-cyclopentyl)-methyl]-3-[(4- SC_2097methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2076CIS-3-[(2-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8- INT-987dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2077CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2132phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-propionamide SC_2078CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2132phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-propionamide SC_2079CIS-8-Dimethylamino-1-[(1-fluoro-cyclobutyl)-methyl]-3-[(4- SC_2097methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2080CIS-1-(2-Cyclohexyl-ethyl)-8-dimethylamino-3-[(4-methoxyphenyl)- SC_2097methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2081CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2082CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-methyl-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2083CIS-8-Dimethylamino-1-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)- SC_2097ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2084CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(2- SC_2097tetrahydro-pyran-4-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one SC_2085CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl- INT-9871,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2086CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[[6- INT-987(trifluoromethyl)-pyridin-3-yl]-methyl]-1,3-diazaspiro[4.5]decan-2- oneSC_2088 CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-SC_2081 1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2090CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(4- SC_2044methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2091CIS-8-Dimethylamino-1-[(1-methoxy-cyclobutyl)-methyl]-3-[(4- SC_2075methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2092CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl- INT-9871,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile SC_2094CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)-methyl]-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2095CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1- SC-2097propyl-1,3-diazaspiro[4.5]decan-2-one SC_2096CIS-3-Benzyl-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3- INT-963diazaspiro[4.5]decan-2-one SC_2099CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1- SC_2097(pyrimidin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2100CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-1-yl]-2,2-dimethyl-propionitrile SC_2101CIS-2-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-benzoic acid methyl esterSC_2102 CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-2-INT-987 yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2103CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-4- INT-987yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2104CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1- SC_2097(tetrahydro-furan-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2105CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyrimidin- INT-9872-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2106CIS-3-[[1-[(5-Cyano-2-methoxy-phenyl)-methyl]-8-dimethylamino- SC_21422-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-4-methoxy-benzonitrile SC_2108CIS-8-Dimethylamino-1-(3-methoxy-3-methyl-butyl)-3-[(4- SC_2107methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2110CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo- SC_21418-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide SC_2111CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2- SC_2097methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2112CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)- SC_2051methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2113CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1- SC_2097(tetrahydro-furan-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2114CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan- INT-9762-one SC_2115 CIS-3-Benzyl-8-dimethylamino-1-ethyl-8-phenyl-1,3- SC_2114diazaspiro[4.5]decan-2-one SC_2117CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[2- SC_2097(methylsulfinyl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2118CIS-8-Dimethylamino-1-[(2R)-2-hydroxy-propyl]-3-[(4- SC_2087methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2119CIS-8-Dimethylamino-1-[(2S)-2-hydroxy-propyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2120CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1- SC_2097(tetrahydro-furan-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one SC_2122CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)-methyl]-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2126CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo- SC_21428-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-4-methoxy- benzonitrileSC_2127CIS-8-Dimethylamino-1-ethyl-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-INT-949 diazaspiro[4.5]decan-2-one SC_2129CIS-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-[(4- SC_2097methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2130CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4- INT-966methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2131CIS-8-Dimethylamino-8-[4-(methoxymethyloxy)-phenyl]-3-[(4- INT-966methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2132CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2133phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid SC_2133CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8- SC_2097phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionic acid tert-butyl esterSC_2134 CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-SC_2044 oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-aceticacid methyl ester SC_2135CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methyl- SC_2097but-2-enyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2137CIS-3-[(3-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8- INT-987dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one SC_2138CIS-2-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo- INT-9878-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile SC_2139CIS-8-Dimethylamino-8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)- INT-966methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2140CIS-8-Dimethylamino-8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)- INT-966methyl]-1,3-diazaspiro[4.5]decan-2-one SC_2141CIS-3-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo- INT-9878-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile SC_2142CIS-3-((8-(dimethylamino)-2-oxo-8-phenyl-1,3- INT-976diazaspiro[4.5]decan-3-yl)methyl)-4-methoxybenzonitrile in analogy tom/z Example Reactant II method [M + H]⁺ SC_2001 — SC_2093 510.3 SC_20032-bromo-propane SC_2014 436.3 SC_2004 cyclopropyl-methylbromide SC_2125448.3 SC_2005 Isobutyraldehyde SC_2028 504.4 SC_2006 — SC_2109 475.3SC_2007 2-(bromomethyl)pyrazine SC_2002 434.3 SC_2009 — SC_2109 475.3SC_2011 (bromomethyl)cyclobutan SC_2010 480.3 SC_2012(bromomethyl)cyclobutan SC_2010 492.3 SC_2013 (bromomethyl)cyclobutanSC_2010 492.3 SC_2015 1-bromobutane SC_2010 450.3 SC_2016dimethylamine/KCN SC_2017 412.2 4-fluorophenylmagnesium bromide SC_20202,5,8,11,14,17-hexaoxanonadecan-19-ol SC_2089 726.5 SC_2021 — SC_2018478.3 SC_2022 1-(bromomethyl)-3-methoxybenzene SC_2019 478.3 SC_2023(bromomethyl)cyclopentane SC_2010 476.3 SC_2024 2,2-dimethyl-oxiraneSC_2010 466.3 SC_2027 (bromomethyl)cyclobutan SC_2010 471.3 SC_2029acetaldehyde SC_2028 476.3 SC_2030 3-bromopropanenitrile SC_2010 447.3SC_2031 — SC_2026 419.3 SC_2032 3-(bromomethyl)oxetane SC_2014 464.3SC_2033 bromomethylpyridine hydrobromide SC_2002 447.3 SC_20351-bromo-2,2-dimethylpropane SC_2014 464.3 SC_2036 1-bromo-3-methylbutaneSC_2010 464.3 SC_2037 1-bromo-3-(trifluoromethoxy)propane SC_2010 520.3SC_2038 2-cyclobutylethyl 4- SC_2010 476.3 methylbenzenesulfonateSC_2039 3-(bromomethyl)-1,1- SC_2010 498.3 difluorocyclobutane SC_20411-bromo-2-methoxyethane SC_2008 506.3 SC_2044 — SC_2026 448.3 SC_2045methyl 2-bromoacetate SC_2010 466.3 SC_2046 NH₄Cl SC_2049 451.3 SC_2047(bromomethyl)benzene SC_2010 484.3 SC_2048 methylamine SC_2049 465.3SC_2050 1-bromo-3-methoxypropane SC_2010 466.3 SC_20511-(bromomethyl)-4-methoxybenzene SC_2019 478.3 SC_20521-bromo-2-methoxyethane SC_2014 452.3 SC_2054 1-bromohexane SC_2014478.3 SC_2055 4-(bromomethyl)tetrahydro-2H-pyran SC_2014 492.3 SC_2056(bromomethyl)cyclohexane SC_2014 490.3 SC_2057 2-aminoacetonitrileSC_2049 490.3 SC_2058 3-(bromomethyl)pyridine SC_2014 485.3 SC_2059dimethylamine/KCN SC_2017 390.3 3-methoxypropyl magnesium bromideSC_2060 2-methoxyethanamine SC_2049 509.3 SC_2062 pyrrolidine SC_2049505.3 SC_2063 dimethylamine SC_2049 479.3 SC_20641-aminocyclopropanecarbonitrile SC_2049 516.3 SC_2065N-methylpropan-1-amine SC_2049 507.3 SC_2066 (bromomethyl)cyclobutaneSC_2125 458.3 SC_2067 (3-bromopropoxy)(tert- SC_2034 452.3butyl)dimethylsilane SC_2068 1-bromo-4-methoxybutane SC_2014 480.3SC_2069 1-(bromo-methyl)-1-methyl-cyclobutane INT-982 476.3 step 1SC_2070 O-tert-butyldimethylsilyl-1-(4- SC_2124 506.3methylbenzenesulfon- oxymethyl)cyclohexanol SC_20715-aminopentanenitrile SC_2014 475.3 SC_2072 NH₄Cl SC_2049 465.3 SC_20741-(aminomethyl)cyclobutane-carbonitrile SC_2014 487.3 SC_2075O-tert-butyldimethylsilyl-1-(4- SC_2124 492.3 methylbenzenesulfon-oxymethyl)cyclopentanol SC_2076 1-bromo-2-(bromomethyl)benzene SC_2002510.2 SC_2077 methylamine SC_2049 479.3 SC_2078 propan-1-amine SC_2049507.3 SC_2079 1-(bromomethyl)-1-fluorocyclobutane SC_2014 480.3 SC_20802-cyclohexylethanamine SC_2014 504.4 SC_2081 3-(aminomethyl)benzonitrileSC_2002 457.3 SC_2082 Iodo-methane SC_2010 408.3 SC_208325-bromo-2,5,8,11,14,17,20,23- SC_2014 760.5 octaoxapentacosane SC_20844-(2-bromoethyl)tetrahydro-2H-pyran SC_2014 506.3 SC_20854-(bromomethyl)benzonitrile SC_2002 457.3 SC_2086 5-(bromomethyl)-2-SC_2002 501.3 (trifluoromethyl)pyridine SC_2088 — SC_2109 475.3 SC_2090acetaldehyde SC_2028 476.3 SC_2091 methyliodide SC_2025 492.3 SC_20922-(aminomethyl)benzonitrile SC_2002 457.3 SC_2094 1-iodo-ethane SC_2010422.3 SC_2095 1-iodopropane SC_2010 436.3 SC_2096cyclobutyl-methylbromide SC_2014 432.3 SC_2099 4-(bromomethyl)pyrimidineSC_2010 486.3 SC_2100 3-amino-2,2-dimethylpropanenitrile SC_2014 475.3SC_2101 methyl 2-(bromomethyl)benzoate SC_2125 542.3 SC_21022-(bromomethyl)pyridine SC_2002 433.3 SC_2103 4-(bromomethyl)pyridineSC_2002 433.3 SC_2104 3-(bromomethyl)tetrahydrofuran SC_2014 478.3SC_2105 2-(bromomethyl)pyrimidine SC_2002 434.3 SC_21063-(bromomethyl)-4-methoxybenzonitrile SC_2125 564.3 SC_2108 MethyliodideSC_2025 494.3 SC_2110 — SC_2109 491.3 SC_21111-bromo-2-(methylsulfonyl)ethane SC_2010 500.3 SC_2112 — SC_2026 464.3SC_2113 (tetrahydrofuran-2-yl)methanamine SC_2014 478.3 SC_2114(bromomethyl)benzene SC_2097 364.2 SC_2115 1-bromoethane SC_2010 392.3SC_2117 1-chloro-2-(methylsulfinyl)ethane SC_2010 484.3 SC_2118(R)-propylene oxide SC_2010 452.3 SC_2119 (S)-propylene oxide SC_2010452.3 SC_2120 3-(bromomethyl)tetrahydrofuran SC_2010 478.3 SC_21221-bromoethane SC_2010 422.3 SC_2126(1-(tert-butyldimethylsilyloxy)cyclo- SC_2124 503.3butyl)methyl-4-methylbenzenesulfonate SC_2127 3-(bromomethyl)pyridineSC_2019 393.3 SC_2129 3-(bromomethyl)pyridine SC_2014 506.3 SC_2130dimethylamine/KCN SC_2017 454.3 3-methoxymethoxy-phenylmagnesium bromideSC_2131 dimethylamine/KCN SC_2017 454.3 4-methoxymethoxy-phenylmagnesiumbromide SC_2132 — SC_2043 466.3 SC_2133 tert-butyl acrylate SC_2042522.3 SC_2134 methyl 2-bromoacetate SC_2040 520.3 SC_21351-bromo-3-methylbut-2-ene SC_2010 462.3 SC_21371-bromo-3-(bromomethyl)benzene SC_2002 510.2 SC_21382-(bromomethyl)benzonitrile SC_2019 473.3 SC_2139 dimethylamine/KCNSC_2017 424.3 3-methoxy-phenylmagnesium bromide SC_2140dimethylamine/KCN SC_2017 424.3 4-methoxy-phenylmagnesium bromideSC_2141 3-(bromomethyl)benzonitrile SC_2019 473.3 SC_21423-(bromomethyl)-4-methoxybenzonitrile SC_2097 419.2

in analogy m/z Example Chemical name Reactant I Reactant II to method ¹HNMR data (M + H)⁺ SC_2146 CIS-8-Methylamino-8-phenyl- SC_2143 SC_20261HNMR (DMSO-d6, 400 MHz), δ (ppm) = 341.4 3-(1H-[1,2,3]triazol-4-yl-14.33 (bs, 1H), 7.67 (s, 1H), 7.38 (d, methyl)-1,3- 2H, J = 7.4 Hz),7.29 (t, 2H, J = 7.56 diazaspiro[4.5]decan-2-one Hz), 7.17 (t, 1H, J =7.12 Hz), 6.65 (s, 1H), 4.30 (s, 2H), 3.10 (s, 2H), 1.92 (t, 2H, J =11.86 Hz), 1.83-1.78 (m, 5H), 1.63 (t, 2H, J = 11.76 Hz), 1.36 (d, 2H, J= 12.12 Hz). SC_2148 CIS-2-[4-[(8-Methylamino-2- SC_2145 SC_2026 1HNMR(DMSO-d6, 400 MHz), δ (ppm) = 398.2 oxo-8-phenyl-1,3- 7.87 (s, 1H), 7.67(bs, 1H), 7.41-7.27 diazaspiro[4.5]decan-3- (m, 5H), 7.17 (t, 1H, J =7.16 Hz), 6.64 yl)-methyl]-1H- (bs, 1H), 5.02 (s, 2H), 4.28 (s, 2H),[1,2,3]triazol-1-yl]- 3.13 (s, 2H), 1.95-1.79 (m, 8H, J = 11.32acetamide Hz), 1.66-1.60 (m, 2H), 1.37 (d, 2H, J = 12.16 Hz). SC_2149CIS-8-Dimethylamino-3-[(4- SC_2097 benzyl SC_2147 1H NMR (600 MHz, DMSO)δ 7.52-7.45 528.3 methoxyphenyl)-methyl]-2- carbonochloridate (m, 2H),7.44-7.37 (m, 2H), 7.38-7.29 (m, oxo-8-phenyl-1,3- 3H), 7.30-7.24 (m,2H), 7.26-7.19 (m, diazaspiro[4.5]decane-1- 1H), 7.21-7.15 (m, 2H),6.93-6.86 (m, carboxylic acid benzyl 2H), 5.23 (s, 2H), 4.28 (s, 2H),3.73 (s, ester 3H), 3.19 (s, 2H), 2.84 (ddd, 2H), 2.63- 2.56 (m, 2H),1.88 (s, 6H), 1.37-1.23 (m, 4H). SC_2150 CIS-3-[[1-(2-Hydroxy- SC_2144SC_2026 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 385.2ethyl)-1H-[1,2,3]triazol-4- 7.88 (s, 1H), 7.39 (d, 2H, J = 7.0 Hz),yl]-methyl]-8-methylamino- 7.29 (t, 2H, J = 7.38 Hz), 7.19-7.17 (m,8-phenyl-1,3- 1H), 6.64 (bs, 1H), 4.99 (t, 1H, J = 5.24diazaspiro[4.5]decan-2-one Hz), 4.35 (t, 2H, 5.32 Hz), 4.27 (s, 2H),3.75-3.73 (m, 2H), 3.12 (s, 2H), 1.94- 1.79 (m, 7H), 1.64 (m, 2H), 1.36(d, 2H, J = 12.2 Hz). SC_2151* CIS-8-Dimethylamino-8- INT-7952-(2-bromo- step 2 of 1H NMR (DMSO-d6): δ 8.64 (br s, 393.3phenyl-3-(2-pyridin-2-yl- step1 ethyl)pyridine INT-795 1H), 8.42-8.41(m, 1H), 7.67-7.63 (m, ethyl)-1,3- 1H), 7.40-7.37 (m, 2H), 7.32-7.26 (m,3H), diazaspiro[4.5]decane-2,4- 7.19-7.16 (m, 2H), 3.63-3.61 (t, 2H),dione 2.92-2.90 (t, 2H), 2.46-2.45 (m, 2H), 1.91 (m, 8H), 1.51 (m, 2H),1.45-1.42 (m, 2H). SC_2152 CIS-8-Dimethylamino-8- SC_2151 step 3 of 1HNMR (DMSO-d6): δ 8.45-8.44 (d, 379.3 phenyl-3-(2-pyridin-2-yl- INT-7951H), 7.69-7.65 (m, 1H), 7.37-7.30 (m, ethyl)-1,3- 4H), 7.26-7.16 (m,3H), 6.65 (br s, 1H), diazaspiro[4.5]decan-2-one 3.37-3.32 (m, 2H), 2.99(s, 2H), 2.86- 2.82 (t, 2H), 2.28 (m, 2H), 1.91 (m, 6H), 1.72-1.71 (m,4H), 1.28-1.26 (m, 2H). SC_2153 CIS-8-Dimethylamino-1-[(1- INT-1012SC_2144 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 483.2 hydroxy-cyclobutyl)-7.92 (s, 1H), 7.36-7.24 (m, 5H), 6.00 (s, methyl]-3-[[1-(2-hydroxy- 1H),4.97 (t, 1H, J = 5.32 Hz), 4.36-4.34 ethyl)-1H-[1,2,3]triazol-4- (m,4H), 3.73 (q, 2H, J = 5.36 Hz), 3.24 yl]-methyl]-8-phenyl-1,3- (s, 2H),3.11 (s, 2H), 2.62 (d, 2H, J = diazaspiro[4.5]decan-2- 14.0 Hz),2.08-1.84 (m, 12H), 1.64-1.61 one (m, 1H), 1.38-1.28 (m, 5H). SC_2154*CIS-8-Dimethylamino-3-[2- INT-795 1-(2-bromoethyl)- step 2 of 1H NMR(DMSO-d6): δ 8.71 (br s, 382.3 (1H-imidazol-1-yl)-ethyl]- step11H-imidazole INT-795 1H), 7.42-7.37 (m, 3H), 7.32-7.26 (m, 8-phenyl-1,3-hydrobromide 3H), 7.00 (s, 1H), 6.79 (s, 1H), 4.15-diazaspiro[4.5]decane-2,4- 4.12 (t, 2H), 3.65-3.62 (t, 2H), 2.46 (m,dione 2H), 1.91 (s, 8H), 1.47-1.37 (m, 4H). SC_2155CIS-2-[4-[[8-Dimethylamino- INT-1012 SC_2145 1HNMR (DMSO-d6, 400 MHz), δ(ppm) = 496.3 1-[(1-hydroxy-cyclobutyl)- 7.91 (s, 1H), 7.67 (s, 1H),7.34-7.24 (m, methyl]-2-oxo-8-phenyl-1,3- 6H), 5.99 (s, 1H), 5.01 (s,2H), 4.36 (s, diazaspiro[4.5]decan-3- 2H), 3.25 (s, 2H), 3.11 (s, 2H),2.62- yl]-methyl]-1H- 2.65 (m, 2H), 2.08-1.86 (m, 12H), 1.64-[1,2,3]triazol-1-yl]- .161 (m, 1H), 1.38-1.18 (m, 5H). acetamide SC_2156CIS-1-[(1-Hydroxy- SC_2153 SC_2026 1HNMR (DMSO-d6, 400 MHz), δ (ppm) =469.3 cyclobutyl)-methyl]-3-[[1- 7.93 (s, 1H), 7.44-7.17 (m, 5H), 6.03(s, (2-hydroxy-ethyl)-1H- 1H), 4.98 (t, 1H), 4.36 (s, 4H), 3.73-[1,2,3]triazol-4-yl]- 3.75 (q, 2H, J = 5.48 Hz), 3.27 (s, 2H),methyl]-8-methylamino-8- 3.20 (s, 2H), 2.11-2.03 (m, 4H), 1.86phenyl-1,3- (bs, 7H), 1.62-1.33 (m, 7H). diazaspiro[4.5]decan-2-oneSC_2157* CIS-8-Dimethylamino-8- INT-795 3-(2-bromo- step 2 of 1H NMR(DMSO-d6): δ 8.65 (br s, 393.3 phenyl-3-(2-pyridin-3-yl- step1ethyl)pyridine INT-795 1H), 8.38-8.37 (m, 1H), 8.28 (d, 1H), ethyl)-1,3-7.54 (d, 1H), 7.40-7.36 (m, 2H), 7.31- diazaspiro[4.5]decane-2,4- 7.24(m, 4H), 3.56 (t, 2H), 2.83 (t, 2H), dione 2.44-2.41 (m, 2H), 1.95-1.90(m, 8H), 1.42-1.35 (m, 4H). SC_2158* CIS-8-Dimethylamino-8- INT-7954-(2-bromo- step 2 of 1H NMR (DMSO-d6): δ 8.67 (br s, 393.3phenyl-3-(2-pyridin-4-yl- step1 ethyl)pyridine INT-795 1H), 8.42-8.40(d, 2H), 7.40-7.36 (m, ethyl)-1,3- 2H), 7.31-7.25 (m, 3H), 7.14-7.12 (d,diazaspiro[4.5]decane-2,4- 2H), 3.60-3.56 (t, 2H), 2.85-2.82 (t, dione2H), 2.45-2.41 (m, 2H), 1.95-1.85 (m, 8H), 1.44-1.35 (m, 4H). SC_2159CIS-2-[4-[[1-(Cyclobutyl- INT-1030 ammonia SC_2145 1HNMR (DMSO-d6, 400MHz), δ (ppm) = 480.1 methyl)-8-dimethylamino-2- 7.86 (s, 1H), 7.66 (s,1H), 7.23-7.33 (m, oxo-8 -phenyl-1,3- 6H), 5.00 (s, 2H), 4.30 (s, 2H),3.09(s, diazaspiro[4.5]decan-3-yl]- 2H), 3.04 (s, 2H), 2.61-2.64 (m,2H), methyl]-1H-[1,2,3]triazol- 1.95.-2.02 (m, 11H), 1.69-1.78 (m, 4H),1-yl]-acetamide 1.28-1.33 (m, 4H). SC_2160 CIS-1-(Cyclobutyl-methyl)-INT-1030 SC_2144 1HNMR (DMSO-d6, 400 MHz), δ (ppm) = 467.08-dimethylamino-3-[[1-(2- 7.87 (s, 1H), 7.23-7.35 (m, 5H), 4.97 (t,hydroxy-ethyl)-1H- 1H, J = 5.28 Hz), 4.34 (t, 2H, J = 5.34[1,2,3]triazol-4-yl]- Hz), 4.29 (s, 2H), 3.71-3.75 (q, 2H),methyl]-8-phenyl-1,3- 3.09 (s, 2H), 3.04-3.05 (d, 2H, J = 7.2diazaspiro[4.5]decan-2- Hz), 1.95-2.05 (m, 11H), 1.67-1.85 (m, one 4H),1.25-.133 (bs, 4H). SC_2161 CIS-2-[4-[[1-[(1-Hydroxy- SC_2155 SC_20261HNMR (DMSO-d6, 400 MHz), δ (ppm) = 482.3 cyclobutyl)-methyl]-8- 7.91(s, 1H), 7.68 (s, 1H), 7.44-7.42 (m, methylamino-2-oxo-8-phenyl- 2H),7.35-7.28 (m, 3H), 7.19-7.16 (m, 1,3-diazaspiro[4.5]decan-3- 1H), 6.03(s, 1H), 5.02 (s, 2H), 4.37 (s, yl]-methyl]-1H- 2H), 3.28 (s, 2H), 3.20(s, 2H), 2.14- [1,2,3]triazol-1-yl]- 2.01 (m, 4H), 1.90-1.84 (m, 7H),1.62- acetamide 1.56 (m, 3H), 1.46.133 (m, 3H). SC_2162CIS-1-(Cyclobutyl-methyl)- SC_2160 SC_2026 1HNMR (DMSO-d6, 400 MHz), δ(ppm) = 453.1 3-[[1-(2-hydroxy-ethyl)-1H- 7.87 (s, 1H), 7.40-7.42 (d,2H, J = 7.64 [1,2,3]triazol-4-yl]- Hz), 7.29 (t, 2H, J = 7.48 Hz), 7.17(t, methyl]-8-methylamino-8- 1H, J = 7.18 Hz), 4.98 (t, 1H, J = 5.32phenyl-1,3- Hz), 4.35 (t, 2H, J = 5.44 Hz), 4.31 (s,diazaspiro[4.5]decan-2-one 2H), 3.71-3.75 (q, 2H), 3.13 (s, 2H),3.07-3.09 (d, 2H, J = 7.36 Hz), 2.53- 2.57 (m, 1H), 2.05-2.32 (m, 3H),1.93-197 (m, 2H), 1.67-1.86 (m, 8H), 1.53-1.60 (m, 2H), 1.22-1.25 (m,2H). SC_2163 CIS-2-[4-[[1-(Cyclobutyl- SC_2159 SC_2026 1HNMR (DMSO-d6,400 MHz), δ (ppm) = 466.3 methyl)-8-methylamino-2- 7.86 (s, 1H), 7.68(s, 1H), 7.27-7.37 (m, oxo-8-phenyl-1,3- 5H), 7.17 (t, 1H, J = 7.10 Hz),5.02 (s, diazaspiro[4.5]decan-3-yl]- 2H), 4.32 (s, 2H), 3.07-3.13 (m,4H), methyl]-1H-[1,2,3]triazol- 2.26 (bs, 1H), 2.05-2.11 (m, 2H), 1.951-yl]-acetamide (bs, 2H), 1.67-1.86 (m, 8H), 1.57-1.60 (m, 2H),1.22-1.25 (m, 2H). SC_2164 CIS-8-Dimethylamino-8- SC_2157 step 3 of 1HNMR (DMSO-d6): δ 8.39-8.37 (m, 379.3 phenyl-3-(2-pyridin-3-yl- INT-7952H), 7.61-7.60 (m, 1H), 7.38-7.23 (m, ethyl)-1,3- 6H), 6.67 (br s, 1H),3.26 (t, 2H), 3.01 diazaspiro[4.5]decan-2-one (s, 2H), 2.72 (t, 2H),2.27 (m, 2H), 1.91 (s, 6H), 1.73-1.71 (m, 4H), 1.28-1.24 (m, 2H).SC_2165 CIS-8-Dimethylamino-3-[2- SC_2154 step 3 of 1H NMR (CDCl3): δ7.45 (s, 1H), 368.2 (1H-imidazol-1-yl)-ethyl]- INT-795 7.38-7.34 (m,2H), 7.31-7.21 (m, 3H), 8-phenyl-1,3- 7.04 (s, 1H), 6.92 (s, 1H), 4.95(br s, diazaspiro[4.5]decan-2-one 1H), 4.12-4.09 (t, 2H), 3.45-3.43 (t,2H), 2.67 (s, 2H), 2.03-1.96 (s, 8H), 1.84-1.68 (m, 4H), 1.38-1.29 (m,2H). SC_2166 CIS-8-Dimethylamino-8- SC_2158 step 3 of 1H NMR (DMSO-d6):δ 8.50-8.48 (m, 379.2 phenyl-3-(2-pyridin-4-yl- INT-795 2H), 7.39-7.35(m, 2H), 7.30-7.27 (m, ethyl)-1,3- 3H), 7.14-7.12 (d, 2H), 4.62 (br s,1H), diazaspiro[4.5]decan-2-one 3.46-3.43 (t, 2H), 2.95 (s, 2H), 2.82-2.78 (t, 2H), 2.17-2.02 (m, 10H), 1.85- 1.75 (m, 2H), 1.41-1.29 (m, 2H).SC_2167 CIS-8-Dimethylamino-8- INT-976 2-(2-bromo- SC_2097 1H NMR(DMSO-d6): δ 8.70 (d, 2H), 380.3 phenyl-3-(2-pyrimidin-2-yl-ethyl)pyrimidine 7.38-7.23 (m, 6H), 6.65 (br s, 1H), 3.45 ethyl)-1,3-(t, 2H), 3.00-2.49 (m, 4H), 2.28 (br m, diazaspiro[4.5]decan-2-one 2H),1.91 (s, 6H), 1.73-1.71 (m, 4H), 1.29-1.27 (m, 2H). SC_2168CIS-8-Dimethylamino-8- INT-976 5-(2-chloro- SC_2097 1H NMR (DMSO-d6): δ9.00 (s, 1H), 380.2 phenyl-3-(2-pyrimidin-5-yl- ethyl)pyrimidine 8.64(s, 2H), 7.38-7.31 (m, 4H), 7.26- ethyl)-1,3- 7.23 (m, 1H), 6.69 (br s,1H), 3.26 (m, diazaspiro[4.5]decan-2-one 2H), 3.05 (s, 2H), 2.74 (t,2H), 2.27 (br m, 2H), 1.92-1.69 (m, 10H), 1.28-1.24 (m, 2H). SC_2169CIS-8-Dimethylamino-1- INT-976 1-(chloromethyl)- SC_2097 1H NMR (600MHz, DMSO) δ 7.92-7.86 470.3 ethyl-3-[(4-methylsulfonyl-4-methylsulfonyl- (for step 1), (m, 2H), 7.50-7.46 (m, 2H), 7.38-7.28(m, phenyl)-methyl]-8-phenyl- benzene (step 1), SC_2010 4H), 7.27-7.19(m, 1H), 4.37 (s, 2H), 1,3-diazaspiro[4.5]decan-2- bromoethane (for step2) 3.19 (s, 3H), 3.15-3.03 (m, 4H), 2.69- one (step 2) 2.60 (m, 2H),2.15-2.06 (m, 2H), 1.97 (s, 6H), 1.38-1.27 (m, 4H), 1.14 (t, 3H).SC_2171 CIS-8-Dimethylamino-8- INT-1023 1-phenylcyclo- SC_2170 1H NMR(DMSO-d6): δ 7.36-7.14 (m, 390.2 phenyl-3-(1-phenyl- propanamine 8H),7.08 (d, 2H), 6.77 (br s, 1H), 3.08 cyclopropyl)-1,3- (step 1) (s, 2H),2.29 (m, 2H), 1.92 (s, 6H), diazaspiro[4.5]decan-2-one 1.79-1.77 (m,4H), 1.35-1.33 (m, 2H), 1.23-1.21(m, 2H), 1.09-1.06 (m, 2H). SC_2172CIS-8-Dimethylamino-1,3- INT-976 1-(bromomethyl)- SC_2097 1H NMR(DMSO-d6): δ 7.32-7.14 (m, 514.2 bis[(2-methoxyphenyl)- 2-methoxybenzene9H), 6.99-6.90 (m, 4H), 4.32-4.27 (m, methyl]-8-phenyl- 4H), 3.84-3.77(m, 6H), 3.14 (s, 2H), 1,3-diazaspiro[4.5]decan-2- 2.58-2.54 (m, 2H),2.03-1.97 (m, 2H), one 1.89 (s, 6H), 1.29-1.22 (m, 4H). SC_2173CIS-8-Dimethylamino-3-[(3- INT-976 1-(bromomethyl)- SC_2097 1H NMR (600MHz, DMSO) δ 7.84-7.79 442.2 methylsurfonyl-phenyl)- 3-methylsulfonyl-(m, 1H), 7.74 (d, 1H), 7.62 (t, 1H), methyl]-8-phenyl-1,3- benzene 7.55(d, 1H), 7.36-7.27 (m, 4H), 7.23 (t, diazaspiro[4.5]decan-2- 1H), 6.99(br s, 1H), 4.33 (s, 2H), 3.19 one (s, 2H), 2.97 (s, 2H), 2.35-2.24 (m,2H), 1.93 (d, 6H), 1.85-1.66 (m, 4H), 1.38- 1.31 (m, 2H). SC_2174CIS-8-Dimethylamino-1-[(1- SC_2170 (1-(tert- INT-799 1H NMR (DMSO-d6): δ7.36-7.14 (m, 476.3 hydroxy-cyclobutyl)- butyldimethyl- (step 1) 10H),5.88 (m, 1H), 3.33 (s, 2H), 3.03 methyl]-3-(1-methyl-1- silyloxy)cyclo-(s, 2H), 2.68-2.64 (m, 2H), 2.09-1.95 (m, phenyl-ethyl)-8-phenyl-1,3-butyl)methyl- 10H), 1.89-1.81 (m, 2H), 1.61-1.56 (m,diazaspiro[4.5]decan-2-one 4-methylbenzene- 7H), 1.48-1.28 (m, 5H).sulfonate SC_2175 CIS-3-[(3-Cyclopropyl- INT-976 1-(bromomethyl)-SC_2097 1H NMR (600 MHz, DMSO) δ 8.17 (s, 403.3 phenyl)-methyl]-8-3-cyclopropyl- 1H), 7.41-7.29 (m, 4H), 7.30-7.20 (m,dimethylamino-8-phenyl- benzene 1H), 7.18 (t, 1H), 6.98-6.89 (m, 3H),1,3-diazaspiro[4.5]decan-2- 6.87 (t, 1H), 4.15 (s, 2H), 2.89 (s, 2H),one 2.28 (s, 2H), 1.97 (s, 6H), 1.91-1.83 (m, 1H), 1.80-1.75 (m, 3H),1.34-1.27 (m, 2H), 0.96-0.88 (m, 2H), 0.65-0.57 (m, 2H). SC_2176CIS-3-(1,3-Benzodioxol-4- INT-976 4-(bromomethyl)- SC_2097 1H NMR (600MHz, DMSO) δ 7.37-7.27 408.2 yl-methyl)-8-dimethylamino-1,3-benzodioxole (m, 4H), 7.27-7.20 (m, 1H), 6.88 (s, 1H), 8-phenyl-1,3-6.83-6.76 (m, 2H), 6.67 (dd, 1H), 5.96 diazaspiro[4.5]decan-2-one (s,2H), 4.18 (s, 2H), 2.95 (s, 2H), 2.30-2.26 (m, 2H), 1.93 (s, 6H), 1.84-1.63 (m, 4H), 1.33 (t, 2H). SC_2177 CIS-8-Dimethylamino-1-[(1- SC_2171(1-(tert- INT-799 1H NMR (DMSO-d6): δ 7.34-7.17 (m, 474.2hydroxy-cyclobutyl)- butyldimethyl- (step 1) 8H), 7.15-7.13 (m, 2H),5.89 (s, 1H), methyl]-8-phenyl-3-(1- silyloxy)cyclo- 3.29 (s, 2H), 3.09(s, 2H), 2.64-2.61 (m, phenyl-cyclopropyl)-1,3- butyl)methyl- 2H),2.08-2.03 (m, 4H), 1.96 (s, 6H), diazaspiro[4.5]decan-2-one4-methylbenzene- 1.91-1.84 (m, 2H), 1.64-1.61 (m, 1H), sulfonate1.42-1.29 (m, 5H), 1.29-1.26 (m, 2H), 1.13-1.01 (m, 2H) SC_2178CIS-4-[[8-Dimethylamino-3- SC_2179 4-(bromo- SC_2097 1H NMR (DMSO-d6): δ7.81 (d, 2H), 509.2 [(2-methoxyphenyl)-methyl]- methyl)benzo- 7.53 (d,2H), 7.32-7.21 (m, 6H), 7.15- 2-oxo-8-phenyl-1,3- nitrile 7.13 (m, 1H),6.99-6.92 (m, 2H), 4.38- diazaspiro[4.5]decan-1- 4.31 (m, 4H), 3.77 (s,3H), 3.16 (s, 2H), yl]-methyl]-benzonitrile 2.58-2.55 (m, 2H), 2.00-1.89(m, 8H), 1.29-1.23 (m, 4H). SC_2179 CIS-8-Dimethylamino-3-[(2- INT-9761-(bromomethyl)- SC_2097 1H NMR (600 MHz, DMSO) δ 7.37-7.27 394.3methoxyphenyl)-methyl]-8- 2-methoxybenzene (m, 4H), 7.27-7.19 (m, 2H),7.08 (dd, phenyl-1,3- 1H), 6.96 (dd, 1H), 6.91 (td, 1H), 6.85diazaspiro[4.5]decan-2-one (s, 1H), 4.19 (s, 2H), 3.75 (s, 3H), 2.96 (s,2H), 2.30 (d, 2H), 1.93 (s, 6H), 1.86-1.69 (m, 4H), 1.38-1.32 (m, 2H).SC_2181 CIS-8-Dimethylamino-8- INT-1028 2-(bromo- SC_2180 1H NMR (600MHz, DMSO) δ 8.48 (ddd, 365.2 phenyl-3-(pyridin-2-yl- methyl)pyridine1H), 7.76 (td, 1H), 7.37-7.27 (m, 4H), methyl)-1,3- hydrobromide7.29-7.17 (m, 3H), 6.93 (s, 1H), 4.30 (s, diazaspiro[4.5]decan-2-one(step 1) 2H), 3.05 (s, 2H), 2.36-2.21 (m, 2H), 1.93 (s, 6H), 1.88-1.58(m, 4H), 1.41- 1.31 (m, 2H). SC_2182 CIS-8-Dimethylamino-8- INT-10283-(bromo- SC_2180 1H NMR (600 MHz, DMSO) δ 8.46 (dd, 365.2phenyl-3-(pyridin-3-yl- methyl)pyridine 1H), 8.42 (dd, 1H), 7.60 (dt,1H), 7.38- methyl)-1,3- hydrobromide 7.30 (m, 3H), 7.31-7.26 (m, 2H),7.26- diazaspiro[4.5]decan-2-one (step 1) 7.20 (m, 1H), 6.97-6.93 (m,1H), 4.24 (s, 2H), 2.95 (s, 2H), 2.33-2.20 (m, 2H), 1.92 (s, 6H),1.84-1.60 (m, 4H), 1.35- 1.29 (m, 2H). SC_2184 CIS-8-Dimethylamino-8-INT-1065 piperidine SC_2183 1H NMR (600 MHz, CDCl3) δ 8.09 (d, 448.3phenyl-3-[(2-piperidin-1- 1H), 7.38 (dd, 2H), 7.30 (d, 3H), 6.48yl-pyridin-4-yl)-methyl]- (s, 1H), 6.42 (dd, 1H), 5.47 (s, 1H),1,3-diazaspiro[4.5]decan-2- 4.23 (s, 2H), 3.54-3.46 (m, 4H), 2.96 (s,one 2H), 2.20-2.15 (m, 4H), 2.07 (s, 6H), 1.92-1.84 (m, 2H), 1.66-1.60(m, 6H), 1.47-1.39 (m, 2H). SC_2185 CIS-8-Dimethylamino-3-[(2- INT-1065morpholine SC_2183 1H NMR (600 MHz, DMSO) δ 8.05 (d, 450.3morpholin-4-yl-pyridin-4- 1H), 7.37-7.27 (m, 4H), 7.26-7.20 (m,yl)-methyl]-8-phenyl-1,3- 1H), 6.94 (s, 1H), 6.59 (s, 1H), 6.50diazaspiro[4.5]decan-2-one (dd, 1H), 4.13 (s, 2H), 3.68 (t, 4H),3.41-3.36 (m, 4H), 2.96 (s, 2H), 2.37- 2.22 (m, 2H), 1.93 (s, 6H),1.86-1.62 (m, 4H), 1.42-1.29 (m, 2H). (*Comparative Example)

Chemical Structure of all Examples

Pharmacological Investigations

Functional investigation on the human mu-opioid receptor (hMOP), humankappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), andhuman nociceptin/orphanin FQ peptide receptor (hNOP)

Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay

The hMOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl(pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin(Sigma-Aldrich Co. St. Louis. Mo.). The final assay volume (250 μl/well)included 1 nM of [N-allyl-2.3-³H]naloxone as ligand (PerkinElmer LifeSciences. Inc. Boston. Mass. USA). and either test compound in dilutionseries or 25 μM unlabelled naloxone for determination of unspecificbinding. The test compound was diluted with 25% DMSO in H₂O to yield afinal 0.5% DMSO concentration. which also served as a respective vehiclecontrol. The assay was started by adding wheat germ agglutinin coatedSPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had beenpreloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc.Boston. Mass. USA). After incubation for 90 minutes at RT andcentrifugation for 20 minutes at 500 rpm the signal rate was measured bymeans of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]naloxone-specificreceptor binding were calculated by nonlinear regression analysis and Kivalues were calculated by using the Cheng-Prusoff equation. (Cheng andPrusoff. 1973).

Human Kappa-Opioid Peptide (hKOP) Receptor Binding Assay

The hKOP receptor binding assay is run as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl(pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of250 μl per well includes 2 nM of [³H]U69,593 as ligand, and either testcompound in dilution series or 100 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hKOP receptor membranes (14.8 μg/250 μl finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 90 minutes at room temperature. After this incubation, themicrotiter plates are sealed with a topseal and centrifuged for 20minutes at 500 rpm. The signal rate is measured after a short delay of 5minutes by means of a 1450 Microbeta Trilux β-counter (PerkinElmer LifeSciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]U69.593-specificreceptor binding are calculated by nonlinear regression analysis and Kivalues are calculated by using the Cheng-Prusoff equation, (Cheng andPrusoff, 1973).

Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay

The hDOP receptor binding assay is performed as homogeneous SPA-assayusing the assay buffer 50 mM TRIS-HCl, 5 mM MgCl₂ (pH 7.4). The finalassay volume (250 μl/well) includes 1 nM of[Tyrosyl-3,5-³H]2-D-Ala-deltorphin II as ligand, and either testcompound in dilution series or 10 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hDOP receptor membranes (15.2 μg/250 μl finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 120 minutes at room temperature and centrifuged for 20minutes at 500 rpm. The signal rate is measured by means of a 1450Microbeta Trilux β-counter (PerkinElmer Life Sciences/Wallac, Turku,Finland). Half-maximal inhibitory concentration (IC50) values reflecting50% displacement of [Tyrosyl-3,5-³H]2-D-Ala-deltorphin II-specificreceptor binding are calculated by nonlinear regression analysis andK_(i) values are calculated by using the Cheng-Prusoff equation, (Chengand Prusoff, 1973).

Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay

The hNOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl.10 mM MgCl₂. 1 mM EDTA (pH 7.4). The final assay volume (250 μl/well)included 0.5 nM of [leucyl-³H]nociceptin as ligand (PerkinElmer LifeSciences. Inc. Boston. Mass. USA). and either test compound in dilutionseries or 1 μM unlabelled nociceptin for determination of unspecificbinding. The test compound was diluted with 25% DMSO in H₂O to yield afinal 0.5% DMSO concentration. which also served as a respective vehiclecontrol. The assay was started by adding wheat germ agglutinin coatedSPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had beenpreloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc.Boston. Mass. USA). After incubation for 60 minutes at RT andcentrifugation for 20 minutes at 500 rpm the signal rate was measured bymeans of a 1450 Microbeta Trilux 1-counter (PerkinElmer LifeSciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]nociceptin-specificreceptor binding were calculated by nonlinear regression analysis and Kivalues were calculated by using the Cheng-Prusoff equation. (Cheng andPrusoff. 1973).

hNOP Ki [nM] hMOP Ki [nM] or % inhibition or % inhibition Example @ 1 μM@ 1 μM SC_2001 2.7 245 SC_2002 4.3 965 SC_2003 585 5875 SC_2004 21.51310 SC_2005 12% @ 1 μM — SC_2006 0.8 43 SC_2007 1.1 43.5 SC_2008 690not determined SC_2009 17.6 385 SC_2010 88.5 not determined SC_2011 50.5880 SC_2012 50 1350 SC_2013 125 18.4 SC_2014 23.5 470 SC_2015 6.4 162.5SC_2017 80 5460 SC_2018 70.8 66.8 SC_2019 0.8 50.8 SC_2020 15.5 305SC_2021 1200 4615 SC_2022 5.4 420 SC_2023 3.8 180 SC_2024 48 1450SC_2025 49.5 920 SC_2026 11 255 SC_2027 12 1415 SC_2028 135 3260 SC_202950 2150 SC_2030 96.5 1260 SC_2031 4.6 139.5 SC_2032 36 1035 SC_2033 27855 SC_2034 490 4025 SC_2035 39 1240 SC_2036 3.1 215 SC_2037 19.5 160SC_2038 13.5 380 SC_2039 2.8 54.5 SC_2040 34 705 SC_2041 195 1925SC_2042 16.5 1275 SC_2043 530 20% @ 1 μM SC_2044 10.8 275 SC_2045 211035 SC_2046 38% @ 1 μM 23% @ 1 μM SC_2047 85.5 600 SC_2048 390 3430SC_2049 24 1570 SC_2050 11.5 310 SC_2051 9 515 SC_2052 26.2 996.7SC_2053 220 1385 SC_2054 43.5 340 SC_2055 96.5 2780 SC_2056 31 545SC_2057 330 5475 SC_2058 49.5 195 SC_2059 4% @ 1 μM 26% @ 1 μM SC_206045 1035 SC_2061 0.5 86.5 SC_2062 20.5 1750 SC_2063 18 3430 SC_2064 412000 SC_2065 27 650 SC_2066 455 90 SC_2067 217.5 4700 SC_2068 34.5 230SC_2069 14 675 SC_2070 18.5 5875 SC_2071 40 860 SC_2072 620 19% @ 1 μMSC_2073 200 3440 SC_2074 3.4 310 SC_2075 9.1 480 SC_2076 51.5 925SC_2077 325 3460 SC_2078 170 563.3 SC_2079 19.3 710 SC_2080 87.5 625SC_2081 1.2 147 SC_2082 180 2390 SC_2083 405 5250 SC_2084 34 880 SC_20853.8 230 SC_2086 3.5 150 SC_2087 47 1365 SC_2088 1.9 110 SC_2089 1.8 73SC_2090 106 3185 SC_2091 26 1620 SC_2092 5.6 380 SC_2093 0.8 53.7SC_2094 19 50.5 SC_2095 11.2 575 SC_2096 1.3 81 SC_2097 91 2645 SC_2099215 5135 SC_2100 11.8 1320 SC_2101 135 1170 SC_2102 3.3 84.5 SC_2103 1.554 SC_2104 22.5 1000 SC_2105 2.4 45 SC_2106 16.5 1540 SC_2107 57 1700SC_2108 10.1 195 SC_2109 17 260 SC_2110 16.5 134 SC_2111 159 1675SC_2112 135 925 SC_2113 4 310 SC_2114 300 3045 SC_2115 720 2480 SC_2117630 not determined SC_2118 195 995 SC_2119 85 90 SC_2120 19 1000 SC_2122310 830 SC_2123 not determined 3840 SC_2124 4 43 SC_2125 3.4 120 SC_2143405 5290 SC_2144 715 5180 SC_2145 340 4940 SC_2146 2%  9% SC_2147 14% 10% SC_2148 8%  0% SC_2149 160 250 SC_2150 6%  4% SC_2152 175 2475SC_2153 22 130 SC_2155 12.5 98 SC_2156 130 330 SC_2159 2.35 40.5 SC_21604 39 SC_2161 100.5 295 SC_2162 31 82.5 SC_2163 13 93.5 SC_2164 130 2765SC_2165 255 2000 SC_2166 106.5 3690 SC_2168 240 13% SC_2169 785 790SC_2170 325 not determined SC_2171 49.25 362.5 SC_2172 50 630 SC_2173145 5245 SC_2174 8.15 235 SC_2175 90.5 1830 SC_2176 110 3090 SC_2177 1899.5 SC_2178 390 1050 SC_2179 108.5 2660 SC_2180 240 4085 SC_2181 19019% SC_2182 250 13% SC_2183 63 3580 SC_2184 25 845 SC_2185 115 6980SC_2186 40 2775

Protocol for [³⁵S]GTPγS Functional NOP/MOP/KOP/DOP Assays

Cell membrane preparations of CHO-K1 cells transfected with the humanMOP receptor (Art.-No. RBHOMM) or the human DOP receptor(Art.-No.RBHODM), and HEK293 cells transfected with the human NOPreceptor (Art.-No.RBHORLM) or the human KOP receptor (Art.-No. 6110558)are available from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1cells transfected with the human nociceptin/orphanin FQ peptide (hNOP)receptor (Art.-No. 93-0264C2, DiscoveRx Corporation, Freemont, Calif.)are also used. [³⁵S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham,Mass.).

The [³⁵S]GTPγS assays are carried out essentially as described by Gillenet al (2000). They are run as homogeneous scintillation proximity (SPA)assays in microtiter luminescence plates, where each well contains 1.5mg of WGA-coated SPA-beads. To test the agonistic activity of testcompounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressingcell membranes from CHO-K1 or HEK293 cells, 10 or 5 μg membrane proteinper assay are incubated with 0.4 nM [³⁵S]GTPγS and serial concentrationsof receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4,100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN₃,and 10 μM GDP for 45 min at room temperature. The microtiter plates arethen centrifuged for 10 min at 830 to sediment the SPA beads. Themicrotiter plates are sealed and the bound radioactivity [cpm] isdetermined after a delay of 15 min by means of a 1450 Microbeta Trilux(PerkinElmer, Waltham, Mass.).

The unstimulated basal binding activity (UBS_(obs) [cpm]) is determinedfrom 12 unstimulated incubates and is set as 100% basal binding. Fordetermination of the potency and the efficacy, the arithmetic mean ofthe observed total [³⁵S]GTPγS binding (TB_(obs) [cpm]) of all incubates(duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ,SNC80, DAMGO, or U69,593) are transformed in percent total binding(TB_(obs) [%]) relative to the basal binding activity (i.e. 100%binding). The potency (EC₅₀) of the respective agonist and its maximalachievable total [³⁵S]GTPγS binding (TB_(calc) [%]) above its calculatedbasal binding (UBS_(calc) [%]) are determined from its transformed data(TB_(obs) [%]) by means of nonlinear regression analysis with XLfit foreach individual concentration series. Then the difference between thecalculated unstimulated [³⁵S]GTPγS binding (UBS_(calc) [%]) and themaximal achievable total [³⁵S]GTPγS binding (TB_(calc) [%]) by eachtested agonist is determined (i.e. B1_(calc) [%]). This difference(B1_(calc) [%]) as a measure of the maximal achievable enhancement of[³⁵S]GTPγS binding by a given agonist is used to calculate the relativeefficacy of test compounds versus the maximal achievable enhancement bya receptor-specific full agonist, e.g. N/OFQ (B1_(calc-N/OFQ) [%]) whichis set as 100% relative efficacy for the hNOP receptor. Likewise, thepercentage efficacies of test compounds at the hDOP, hMOP, or hKOPreceptor are determined versus the calculated maximal enhancement of[³⁵S]GTPγS binding by the full agonists SNC80 (B1_(calc-SNC80) [%]),DAMGO (B1_(calc-DAMGO) [%]) and U69,593 (B1_(calc-U69,593) [%]) whichare set as 100% relative efficacy at each receptor, respectively.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A compound according to general formula (I)

wherein n means 1, 2 or 3; R¹ and R² independently of one another mean—H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted or substituted with one,two, three or four substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and—CO₂CH₃; wherein said 3-12-membered cycloalkyl moiety is optionallyconnected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted; or a 3-12-membered heterocycloalkyl moiety,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃;wherein said 3-12-membered heterocycloalkyl moiety is optionallyconnected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted; or R¹ and R² together with the nitrogen atomto which they are attached form a ring and mean —(CH₂)₃₋₆—;—(CH₂)₂—O—(CH₂)₂—; or —(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br and —I; R³ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; a 3-12-memberedcycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; a3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁴means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—; a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 6-14-membered aryl moiety is optionallyconnected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; R⁵ means a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted; or a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; R⁷, R⁸, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹,and R²⁰ independently of one another mean —H, —F, —Cl, —Br, —I, —OH, or—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein R⁷ and R⁸ togetherwith the carbon atom to which they are attached form a ring and mean—(CH₂)₂— or —(CH₂)₃—; wherein “mono- or polysubstituted” means that oneor more hydrogen atoms are replaced by a substituent independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—R²¹, —C(═O)R²¹, —C(═O)OR²¹, —C(═O)NR²¹R²², —O—(CH₂CH₂—O)₁₋₃₀—H,—O—(CH₂CH₂—O)₁₋₃₀—CH₃, ═O, —OR²¹, —OC(═O)R²¹, —OC(═O)OR²¹,—OC(═O)NR²¹R²², —NO₂, —NR²¹R²², —NR²¹—(CH₂)₁₋₆—C(═O)R²²,—NR²¹—(CH₂)₁₋₆—C(═O)OR²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²¹C(═O)R²²,—NR²¹C(═O)—OR²², —NR²³C(═O)NR²¹R²², —NR²¹S(═O)₂R²², —SR²¹, —S(═O)R²¹,—S(═O)₂R²¹, —S(═O)₂OR²¹, and —S(═O)₂NR²¹R²²; wherein R²¹, R²² and R²³independently of one another mean —H; —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, and—O—C₁-C₆-alkyl; a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted; wherein said 3-12-membered cycloalkyl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl; a 3-12-membered heterocycloalkyl moiety, saturatedor unsaturated, unsubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;wherein said 6-14-membered aryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, —C₁-C₆-alkyland —O—C₁-C₆-alkyl; or R²¹ and R²² within —C(═O)NR²¹R²², —OC(═O)NR²¹R²²,—NR²¹R²², —NR²³—(CH₂)₁₋₆—C(═O)NR²¹R²², —NR²³C(═O)NR²¹R²², or—S(═O)₂NR²¹R²² together with the nitrogen atom to which they areattached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I; or aphysiologically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R⁷, R⁸, R¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, andR²⁰ independently of one another mean —H, —F, —OH, or —C₁-C₆-alkyl; orR⁷ and R⁸ together with the carbon atom to which they are attached forma ring and mean —(CH₂)₂—.
 3. The compound according to claim 1, whereinR¹ means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted.
 4. The compoundaccording to claim 1, wherein R¹ means —CH₃; and R² means —C₁-C₆-alkyl,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 5. The compound according to claim 1, wherein R¹ means—H or —CH₃; and wherein R² means —CH₂-cycloalkyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂-oxetanyl or —CH₂-tetrahydrofuranyl.
 6. Thecompound according to claim 1, wherein R¹ and R² together with thenitrogen atom to which they are attached form a ring and mean—(CH₂)₃₋₆—.
 7. The compound according to claim 1, wherein R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 8. The compound according toclaim 1, wherein R³ means a 6-14-membered aryl moiety, unsubstituted,mono- or poly-substituted.
 9. The compound according to claim 1, whereinR³ means a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted.
 10. The compound according to claim 1, wherein R⁴ means—H.
 11. The compound according to claim 1, wherein R⁴ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 12. The compound according toclaim 1, wherein R⁴ means a 3-12-membered cycloalkyl moiety, saturatedor unsaturated, unsubstituted, mono- or polysubstituted; wherein the3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 13. The compound according to claim 1, wherein R⁴ meansa 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 14. The compound according to claim 1, wherein R⁴ meansa 6-14-membered aryl moiety, unsubstituted, mono- or poly-substituted;wherein said 6-14-membered aryl moiety is connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted.
 15. The compound according toclaim 1, wherein R⁴ means a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted; wherein said 5-14-memberedheteroaryl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 16. The compound according to claim 1, wherein n means1 or
 2. 17. The compound according to claim 1, wherein R⁵ means -phenyl,unsubstituted, mono- or polysubstituted.
 18. The compound according toclaim 1, wherein R⁵ means -pyrazinyl, -pyridazinyl, -pyridinyl,-pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl ineach case unsubstituted, mono- or polysubstituted.
 19. The compoundaccording to claim 1, which has a structure according to any of generalformulas (II-A) to (VIII-C):

wherein in each case R¹, R², R³, R⁴, and R⁵ are defined as in claim 1,R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; R^(D) means —H or —F; or aphysiologically acceptable salt thereof.
 20. The compound according toclaim 1, wherein R⁵ is selected from the group consisting of:


21. The compound according to claim 1, wherein n means 1 or 2; R¹ means—H or —CH₃; R² means —H or —C₁-C₆-alkyl, linear or branched, saturatedor unsaturated, unsubstituted or monosubstituted with —OH, —OCH₃,—C(═O)OCH₃, or —CN; R³ means —C₁-C₄-alkyl, optionally monosubstitutedwith —OCH₃; -phenyl, -thienyl or -pyridinyl, in each case unsubstitutedor substituted with one, two, three or four substituents independentlyof one another selected from the group consisting of —F, —Cl, —CN, —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH, —OCH₃, —O—CH₂—O—CH₃, —C(═O)NH₂,C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH,SOCH₃ and SO₂CH₃; or R⁴ means —H; —C₁-C₆-alkyl, linear or branched,saturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —O—C₁-C₄-alkyl, —CO₂H,—C(═O)O—C₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NH—C₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —C(═O)NH—C₁-C₄-alkyl-CN,—C(═O)NCH₃—C₁-C₄-alkyl-CN, —C(═O)NH-cyclopropyl-CN,—C(═O)NCH₃-cyclopropyl-CN, —C(═O)NH—C₁-C₄-alkyl-OH,—C(═O)NCH₃—C₁-C₄-alkyl-OH, —C(═O)NH—C₁-C₄-alkyl-OCH₃,—C(═O)NCH₃—C₁-C₄-alkyl-OCH₃, —C(═O)NRR′ wherein R and R′ together withthe nitrogen atom to which they are attached form a ring and mean—(CH₂)₂₋₄—; 3-6-membered cycloalkyl, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and—O—C₁-C₄-alkyl, wherein said 3-6-membered cycloalkyl is connectedthrough —C₁-C₆-alkylene; 3-6-membered heterocycloalkyl, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—CO₂H, —C(═O)O—C₁-C₄-alkyl, —OH, and —O—C₁-C₄-alkyl, wherein said3-6-membered heterocycloalkyl is connected through —C₁-C₆-alkylene;6-14-membered aryl, unsubstituted or substituted with one, two, three orfour substituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —CO₂H, —C(═O)O—C₁-C₄-alkyl, —OH,and —O—C₁-C₄-alkyl; wherein said 6-14-membered aryl is connected through—C₁-C₆-alkylene- or —S(═O)₂—; 5-14-membered heteroaryl, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—CO₂H, —C(═O)O—C₁-C₄-alkyl, —OH, and —O—C₁-C₄-alkyl; wherein said5-14-membered heteroaryl is connected through —C₁-C₆-alkylene- or—S(═O)₂—; R⁵ means -phenyl, -pyrazinyl, -pyridazinyl, -pyridinyl,-pyrimidinyl, -thienyl, -imidazolyl, triazolyl, or -1,3-benzodioxolyl,in each case unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F; —Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —CF₃;—C₁-C₄-alkyl-OH; —C₁-C₄-alkyl-C(═O)NH₂; -3-12-membered cycloalkyl,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably -cyclopropyl, saturated, unsubstituted; -3-12-memberedheterocycloalkyl, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; —O—CH₂—O—; —O—C₁-C₄-alkyl; —O—(CH₂CH₂—O)₁₋₃₀—H;—O—(CH₂CH₂—O)₁₋₃₀-CH₃; —C(═O)OH; —C(═O)OC₁-C₄-alkyl; —C(═O)NH₂;—C(═O)NHC₁-C₄-alkyl; —C(═O)N(C₁-C₄-alkyl)₂; —SC₁-C₄-alkyl;—S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; and R⁷, R⁸, R¹¹, R¹², R¹³, R⁴,R¹⁵, R¹⁶, R¹⁷, R⁸, R¹⁹, and R²⁰ mean —H.
 22. The compound according toclaim 1, which has a structure according to general formula (I′)

wherein R¹ to R⁵, R⁷, R⁸, R¹⁰ to R²⁰ and n are defined as in claim 1, ora physiologically acceptable salt thereof.
 23. The compound according toclaim 1, which has a structure according to general formula (IX)

wherein R^(C) means —H or —OH; R³ means -phenyl or -3-fluorophenyl; andR⁵ means 6-14-membered aryl, unsubstituted, mono- or polysubstituted; or5-14-membered heteroaryl, unsubstituted, mono- or polysubstituted; or aphysiologically acceptable salt thereof.
 24. The compound according toclaim 23, wherein R⁵ is selected from -phenyl, -pyridyl, pyrimidinyl, or-triazolyl, in each case unsubstituted, mono- or polysubstituted. 25.The compound according to claim 1, which is selected from the groupconsisting of CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-isopropyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclopropyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-[methyl-(2-methyl-propyl)-amino]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyrazin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-(Allyl-methyl-amino)-1-(cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-methyl-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-Butyl-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-(4-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-(3-fluorophenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(3-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[3-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-(4-hydroxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-onehydrochloride;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclopentyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-(2-hydroxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-(2-methoxy-2-methyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[[1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile;CIS-1-(Cyclobutyl-methyl)-3-[(3-methoxyphenyl)-methyl]-8-(methyl-propyl-amino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(3-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionitrile;CIS-1-(Cyclobutyl-methyl)-8-methylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(oxetan-3-yl-methyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-(2-hydroxy-ethyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-(2,2-dimethyl-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methyl-butyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-[3-(trifluoromethyloxy)-propyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(2-Cyclobutyl-ethyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-[(3,3-Difluoro-cyclobutyl)-methyl]-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-acetonitrile;CIS-1-(Cyclobutyl-methyl)-8-[(2-methoxy-ethyl)-methyl-amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid tert-butyl ester;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid; 2,2,2-trifluoro-acetic acid salt;CIS-1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-aceticacid methyl ester;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide;CIS-1-Benzyl-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-acetamide;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-acetamide;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methoxy-propyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-(2-methoxy-ethyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetonitrile;CIS-8-Dimethylamino-1-hexyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-pyran-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclohexyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-N-(Cyano-methyl)-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3-methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-(2-methoxy-ethyl)-acetamide;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N,N-dimethyl-acetamide;CIS-N-(1-Cyano-cyclopropyl)-2-[8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-acetamide;CIS-2-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-N-propyl-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-(3-methoxy-propyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-(3-hydroxy-propyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-(4-methoxy-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[(1-methyl-cyclobutyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclohexyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-5-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-pentanenitrile;CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionamide;CIS-1-(Cyclobutyl-methyl)-8-[(2-hydroxy-ethyl)-methyl-amino]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-cyclobutane-1-carbonitrile;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclopentyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[(2-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-methyl-propionamide;CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-N-propyl-propionamide;CIS-8-Dimethylamino-1-[(1-fluoro-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(2-Cyclohexyl-ethyl)-8-dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-methyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(2-tetrahydro-pyran-4-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[[6-(trifluoromethyl)-pyridin-3-yl]-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[4-[2-[2-[2-[2-[2-[2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-ethoxy]-phenyl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(4-hydroxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-(ethyl-methyl-amino)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[(1-methoxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzonitrile;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-propyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-Benzyl-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(pyrimidin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-2,2-dimethyl-propionitrile;CIS-2-[[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-benzoicacid methyl ester;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyridin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-(pyrimidin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[[1-[(5-Cyano-2-methoxy-phenyl)-methyl]-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-4-methoxy-benzonitrile;CIS-8-Dimethylamino-1-(3-hydroxy-3-methyl-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-(3-methoxy-3-methyl-butyl)-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-benzamide;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(2-methylsulfonyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-furan-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-3-Benzyl-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-Benzyl-8-dimethylamino-1-ethyl-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-[2-(methylsulfinyl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[(2R)-2-hydroxy-propyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[(2S)-2-hydroxy-propyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(tetrahydro-furan-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-ethyl-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Amino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(2-phenyl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-8-phenyl-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-4-methoxy-benzonitrile;CIS-8-Dimethylamino-1-ethyl-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[2-(1-methoxy-cyclobutyl)-ethyl]-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-[3-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-[4-(methoxymethyloxy)-phenyl]-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionicacid;CIS-3-[8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-propionicacid tert-butyl ester;CIS-2-[[1-(Cyclobutyl-methyl)-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-8-yl]-methyl-amino]-aceticacid methyl ester;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-1-(3-methyl-but-2-enyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[(3-methylsulfanyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[(3-Bromophenyl)-methyl]-1-(cyclobutyl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile;CIS-8-Dimethylamino-8-(3-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-(4-methoxyphenyl)-3-[(4-methoxyphenyl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-3-((8-(dimethylamino)-1-((1-hydroxycyclobutyl)methyl)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)benzonitrile;CIS-3-((8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)methyl)-4-methoxybenzonitrile;CIS-8-Dimethylamino-8-phenyl-3-(1H-[1,2,3]triazol-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[4-[(8-Dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide;CIS-8-Methylamino-8-phenyl-3-(1H-[1,2,3]triazol-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-8-phenyl-1-(p-tolylsulfonyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[4-[(8-Methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide;CIS-8-Dimethylamino-3-[(4-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decane-1-carboxylicacid benzyl ester;CIS-3-[[1-(2-Hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-pyridin-2-yl-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-2-pyridin-2-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[2-(1H-imidazol-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione;CIS-2-[4-[[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide;CIS-1-[(1-Hydroxy-cyclobutyl)-methyl]-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;CIS-2-[4-[[1-(Cyclobutyl-methyl)-8-dimethylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide;CIS-1-(Cyclobutyl-methyl)-8-dimethylamino-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[4-[[1-[(1-Hydroxy-cyclobutyl)-methyl]-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide;CIS-1-(Cyclobutyl-methyl)-3-[[1-(2-hydroxy-ethyl)-1H-[1,2,3]triazol-4-yl]-methyl]-8-methylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-2-[4-[[1-(Cyclobutyl-methyl)-8-methylamino-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-methyl]-1H-[1,2,3]triazol-1-yl]-acetamide;CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-3-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[2-(1H-imidazol-1-yl)-ethyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-(2-pyridin-4-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-2-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-(2-pyrimidin-5-yl-ethyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-ethyl-3-[(4-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-(1-methyl-1-phenyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-(1-phenyl-cyclopropyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1,3-bis[(2-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(3-methylsulfonyl-phenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-3-(1-methyl-1-phenyl-ethyl)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-[(3-Cyclopropyl-phenyl)-methyl]-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-3-(1,3-Benzodioxol-4-yl-methyl)-8-dimethylamino-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-8-phenyl-3-(1-phenyl-cyclopropyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-4-[[8-Dimethylamino-3-[(2-methoxyphenyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-1-yl]-methyl]-benzonitrile;CIS-8-Dimethylamino-3-[(2-methoxyphenyl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-(pyridin-4-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-(pyridin-2-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-(pyridin-3-yl-methyl)-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[[2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-[(2-piperidin-1-yl-pyridin-4-yl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-3-[(2-morpholin-4-yl-pyridin-4-yl)-methyl]-8-phenyl-1,3-diazaspiro[4.5]decan-2-one;CIS-8-Dimethylamino-8-phenyl-3-[(2-piperazin-1-yl-pyridin-4-yl)-methyl]-1,3-diazaspiro[4.5]decan-2-one;and the physiologically acceptable salts thereof.
 26. The compoundaccording to claim 1 for use in the treatment of pain.
 27. A medicamentcomprising a compound according to claim 1.